Vinyl substituted fatty acids

ABSTRACT

Activated fatty acids, pharmaceutical compositions including activated fatty acids, methods for using activated fatty acids to treat a variety of diseases, and methods for preparing activated fatty acids are provided herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/433,130 filed Apr. 30, 2009, which claims priority to U.S.Provisional Patent Application No. 61/049,649 filed May 1, 2008 which isherein incorporated by reference in its entirety.

GOVERNMENT INTERESTS

Not Applicable

PARTIES TO A JOINT RESEARCH AGREEMENT

Not Applicable

INCORPORATION BY REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC

Not Applicable

BACKGROUND

1. Field of Invention

Not applicable

2. Description of Related Art

Nitric oxide (NO) is an endogenously generated, lipophilic signalingmolecule that has been implicated in the maintenance of vascularhomeostasis, modulation of oxygen radical reactions, inflammatory cellfunction, post-translational protein modification and regulation of geneexpression. In addition, nitric oxide-derived species display separateand unique pharmacological properties, specifically can mediateoxidation and nitration of biomolecules such as, for example,unsaturated fatty acids.

Various reactions yield products capable of concerted oxidation,nitrosation and nitration of target molecules. For example, nitric oxidemay react with superoxide (O₂ ⁻) to yield peroxynitrite (ONOO⁻) and itsconjugate acid, peroxynitritrous acid (ONOOH), the latter of which mayundergo homolytic scission to form nitrogen dioxide (.NO₂) and hydroxylradical (.OH). In some instances, biological conditions may favor thereaction of ONOO⁻ with CO₂ which yields nitrosoperoxycarbonate (ONOOCO₂⁻), which rapidly yields .NO₂ and carbonate (.CO₃ ⁻) radicals viahomolysis or rearrangement to NO₃ ⁻ and CO₂. During inflammation,neutrophil myeloperoxidase and heme proteins such as myoglobin andcytochrome c catalyze H₂O₂-dependent oxidation of nitrite (NO₂ ⁻) to.NO₂, resulting in biomolecule oxidation and nitration that isinfluenced by the spatial distribution of catalytic heme proteins. Thereaction of .NO with O₂ can also produce products that can be substratesor reactants for nitrosation and nitration. For example, the smallmolecular radius, uncharged nature and lipophilicity of .NO and O₂facilitate concentration of these species in biological membranes in aprocess referred to as the “molecular lens” effect. The increase inconcentration induced by .NO and O₂ solvation in hydrophobic cellcompartments accelerates the normally slow reaction of .NO with O₂ toyield N₂O₃ and N₂O₄. Finally, environmental sources also yield .NO₂ as aproduct of photochemical air pollution and tobacco smoke.

Nitration of fatty acids by .NO₂ can occur through several methods. Forexample, during both basal cell signaling and tissue inflammatoryconditions, .NO₂ can react with membrane and lipoprotein lipids. In bothin vivo and in vitro systems, .NO₂ has been shown to initiate radicalchain auto-oxidation of polyunsaturated fatty acids via hydrogenabstraction from the bis-allylic carbon to form nitrous acid and aresonance-stabilized bis-allylic radical. Depending on the radicalenvironment, the lipid radical species can react with molecular oxygento form a peroxyl radical, which can react further to form lipidhydroperoxides then oxidized lipids. During inflammation or ischemia,when O₂ levels are lower, lipid radicals can react to an even greaterextent with .NO₂ to generate multiple nitration products includingsingly nitrated, nitrohydroxy- and dinitro-fatty acid adducts. Theseproducts can be generated via hydrogen abstraction, direct addition of.NO₂ across the double bond, or both, and in some cases, such reactionsmay be followed by further reactions of the intermediate products thatare formed. Hydrogen abstraction causes a rearrangement of the doublebonds to form a conjugated diene; however, the addition of .NO₂maintains a methylene-interrupted diene configuration to yield singlynitrated polyunsaturated fatty acids. This arrangement is similar tonitration products generated by the nitronium ion (NO₂ ⁺), which can beproduced by ONOO⁻ reaction with heme proteins or via secondary productsof CO₂ reaction with ONOO⁻.

The reaction of polyunsaturated fatty acids with acidified nitrite(HNO₂) can generate a complex mixture of products similar to thoseformed by direct reaction with .NO₂, including the formation of singlynitrated products that maintain the bis-allylic bond arrangement. Theacidification of NO₂ can create a labile species, HNO₂, which is inequilibrium with secondary products, including N₂O₃, .NO and .NO₂, allof which can participate in nitration reactions. The relevance of thispathway as a mechanism of fatty acid nitration is exemplified byphysiological and pathological conditions wherein NO₂ is exposed to lowpH (e.g., <pH 4.0). This may conceivably occur in the gastriccompartment, following endosomal or phagolysosomal acidification or intissues following-post ischemic reperfusion.

Nitrated linoleic acid (LNO₂) has been shown to display robust cellsignaling activities that are generally anti-inflammatory in nature.Synthetic LNO₂ can inhibit human platelet function via cAMP-dependentmechanisms and inhibits neutrophil O₂ ⁻ generation, calcium influx,elastase release, CD11b expression and degranulation via non-cAMP,non-cGMP-dependent mechanisms. LNO₂ may also induce vessel relaxation inpart via cGMP-dependent mechanisms. In aggregate, these data, derivedfrom a synthetic fatty acid infer that nitro derivatives of fatty acids(NO₂—FA) represent a novel class of lipid-derived signaling mediators.To date, a gap in the clinical detection and structural characterizationof nitrated fatty acids has limited defining NO₂—FA derivatives asbiologically-relevant lipid signaling mediators that converge .NO andoxygenated lipid signaling pathways.

BRIEF SUMMARY OF THE INVENTION

Various embodiments of the invention are directed to compounds includinga non-naturally occurring, unsaturated or polyunsaturated fatty acidhaving one or more electron withdrawing group associated with at leastone carbon-carbon double bond or a pharmaceutically acceptable saltthereof. In some embodiments, the non-naturally occurring, unsaturatedor polyunsaturated fatty acid may include an aliphatic chain having anodd number of carbons, and in other embodiments, the non-naturallyoccurring, unsaturated or polyunsaturated fatty acid may include analiphatic chain having 5 to 23 carbons or, in certain embodiments, analiphatic chain having 5, 7, 9, 11, 13, 15, 17, 19, 21 or 23 carbons. Inadditional embodiments, the non-naturally occurring unsaturated orpolyunsaturated fatty acid may be a glycolipid, a glycerolipid, aphospholipid and a cholesterol ester.

The one or more electron withdrawing group of various embodiments mayinclude, but are not limited to, aldehyde (—COH), acyl (—COR), carbonyl(—CO), carboxylic acid (—COOH), ester (—COOR), halides (—Cl, —F, —Br,—I), fluoromethyl (—CF_(n)), allyl fluoride (—CH═CHCH₂F), cyano (—CN),sulfoxide (—SOR), sulfonyl (—SO₂R), sulfonic acid (—SO₃H), 1°, 2° and 3°ammonium (—NR₃ ⁺), or nitro (—NO₂), wherein R is a hydrogen, methyl orC₂-C₆ alkyl, and in particular embodiments, the one or more electronwithdrawing group may be a nitro (—NO₂) group. In some embodiments, theone or more electron withdrawing group may be positioned on an alphacarbon of a carbon-carbon double bond of the non-naturally occurring,unsaturated or polyunsaturated fatty acid, and in other embodiments, theone or more electron withdrawing group may be positioned on a betacarbon of a carbon-carbon double bond of the non-naturally occurring,unsaturated or polyunsaturated fatty acid. In still other embodiments,the one or more electron withdrawing group may be positioned on a gammacarbon of a carbon-carbon double bond of the non-naturally occurring,unsaturated or polyunsaturated fatty acid. In certain embodiments, theat least one of the one or more electron withdrawing group may be anelectron withdrawing vinyl group or an electron withdrawing allylicgroup. In some embodiments, a carbon-carbon double bond associated withthe one or more electron withdrawing group may be in cis configuration,and in others, a carbon-carbon double bond associated with the one ormore electron withdrawing group may be in trans configuration. In stillother embodiments, the one or more electron withdrawing group may be inan absolute stereochemistry of R at an sp³ chiral/stereogenic center,and in some other embodiments, the one or more electron withdrawinggroup may be in an absolute stereochemistry of S at an sp³chiral/stereogenic center.

In various embodiments, a carbon-carbon double bond may occur at anycarbon of the aliphatic chain of the non-naturally occurring,unsaturated or polyunsaturated fatty acid. In some embodiments, thenon-naturally occurring, unsaturated or polyunsaturated fatty acid maybe a fatty acid with two or more conjugated carbon-carbon double bonds,and in particular embodiments, at least one of the one or more electronwithdrawing group may be at any carbon in the two or more conjugatedcarbon-carbon double bonds. In certain embodiments, at least one of theone or more electron withdrawing group may be positioned at C-9, C-10,C-12, C-13 or a combination thereof.

In some embodiments, one or more non-carbon-carbon linkage such as, forexample, an ester linkage, an ether linkage, and a vinyl ether linkagemay be substituted on the aliphatic chain of the non-naturallyoccurring, unsaturated or polyunsaturated fatty acid, and in otherembodiments, the non-naturally occurring, unsaturated or polyunsaturatedfatty acid may further include one or more functional group other thanan electron withdrawing group positioned at any carbon of the aliphaticchain of the non-naturally occurring, unsaturated or polyunsaturatedfatty acid.

In particular embodiments, the non-naturally occurring, unsaturated orpolyunsaturated fatty acid having one or more electron withdrawing groupor a pharmaceutically acceptable salt thereof further include apharmaceutically acceptable carrier or excipient. In other embodiments,the non-naturally occurring, unsaturated or polyunsaturated fatty acidmay further include one or more of diluents, fillers, disintegrants,binders, lubricants, surfactants, hydrophobic vehicles, water solublevehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers,antioxidants, preservatives or combinations thereof, and in still otherembodiments, the non-naturally occurring, unsaturated or polyunsaturatedfatty acid having one or more electron withdrawing group or apharmaceutically acceptable salt thereof further including apharmaceutically acceptable carrier or excipient may be formulated as,for example, a solid, solution, powder, fluid emulsion, fluidsuspension, semi-solid or dry powder.

Various embodiments of the invention further include a compoundcomprising an unsaturated or polyunsaturated fatty acid having one ormore electron withdrawing group associated with at least one double bondor a pharmaceutically acceptable salt thereof, with the proviso that theelectron withdrawing group associated with the at least one double bondis not a nitro (—NO₂) group. In some embodiments, the unsaturated orpolyunsaturated fatty acid may include a naturally occurring fatty acidor derivative thereof, and in such embodiments, the unsaturated orpolyunsaturated fatty acid may include an aliphatic carbon chain havingan even number of carbons. In particular embodiments, the unsaturated orpolyunsaturated fatty acid may include an aliphatic carbon chain havingfrom 4 to 24 carbons, and in other embodiments, the unsaturated orpolyunsaturated fatty acid comprises an aliphatic carbon chain havingfrom 12 to 18 carbons. In certain embodiments, the unsaturated orpolyunsaturated fatty acid may be, for example, a ω-2, ω-3, ω-4, ω-5,ω-6, ω-7, ω-8, ω-9 fatty acids and equivalents and derivatives thereof.For example, in some embodiments, the unsaturated or polyunsaturatedfatty acid may be linolenic acid, alpha-linolenic acid, eicosapentanoicacid, docosapentaenoic acid, docosahexaenoic acid, stearidonic acid,myristoleic acid, linoleic acid, gamma-linoleic acid,dihomo-gamma-linoleic acid, arachidonic acid, palmitoleic acid, oleicacid, erucic acid and equivalents and derivatives thereof, and in otherembodiments, the unsaturated fatty acid is selected from linoleic acid,oleic acid, arachidonic acid or a derivative thereof. In still otherembodiments, the unsaturated or polyunsaturated fatty acid may be, forexample, a glycolipid, a glycerolipid, a phospholipid and a cholesterolester.

In some embodiments, the at least one electron withdrawing group may bepositioned at C-9, C-10, C-12, C-13 or a combination thereof, and inother embodiments, the unsaturated or polyunsaturated fatty acid mayinclude one or more non-carbon-carbon linkage selected from an esterlinkage, an ether linkage, a vinyl ether linkage or a combinationthereof.

In various embodiments, the one or more electron withdrawing group maybe, for example, aldehyde (—COH), acyl (—COR), carbonyl (—CO),carboxylic acid (—COOH), ester (—COOR), halides (—Cl, —F, —Br, —I),fluoromethyl (—CF_(n)), allyl fluoride (—CH═CHCH₂F), cyano (—CN),sulfoxide (—SOR), sulfonyl (—SO₂R), sulfonic acid (—SO₃H), and 1°, 2°and 3° ammonium (—NR₃ ⁺), wherein R is a hydrogen, methyl or C₂-C₆alkyl. In some embodiments, the one or more electron withdrawing groupmay be positioned on an alpha carbon of a carbon-carbon double bond ofthe unsaturated or polyunsaturated fatty acid. In other embodiments, theone or more electron withdrawing group may be positioned on a betacarbon of a carbon-carbon double bond of the unsaturated orpolyunsaturated fatty acid, and in still other embodiments, the one ormore electron withdrawing group is positioned on a gamma carbon of acarbon-carbon double bond of the unsaturated or polyunsaturated fattyacid. In yet other embodiments, the at least one of the one or moreelectron withdrawing group may be an electron withdrawing vinyl group oran electron withdrawing allylic group.

In certain embodiments, a carbon-carbon double bond associated with theone or more electron withdrawing group may be in cis configuration, andin some embodiments, a carbon-carbon double bond associated with the oneor more electron withdrawing group may be in trans configuration. Inother embodiments, the one or more electron withdrawing group may be inan absolute stereochemistry of R at an sp³ chiral/stereogenic center,and in still other embodiments, the one or more electron withdrawinggroup may be in an absolute stereochemistry of S at an sp³chiral/stereogenic center.

A carbon-carbon double bond may occurs at any carbon of the aliphaticchain of the naturally occurring, unsaturated or polyunsaturated fattyacid in various embodiments, of the invention. In some embodiments, theunsaturated or polyunsaturated fatty acid may be a fatty acid with twoor more conjugated carbon-carbon double bonds, and in other embodiments,at least one of the one or more electron withdrawing group may be at anycarbon in the two or more conjugated carbon-carbon double bonds.

In particular embodiments, the unsaturated or polyunsaturated fatty acidhaving one or more electron withdrawing group associated with at leastone double bond or a pharmaceutically acceptable salt thereof mayfurther include a pharmaceutically acceptable carrier or excipient. Insome embodiments, the unsaturated or polyunsaturated fatty acid havingone or more electron withdrawing group associated with at least onedouble bond or a pharmaceutically acceptable salt thereof may furtherinclude one or more of diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,antioxidants, preservatives or combinations thereof, and in otherembodiments, the unsaturated or polyunsaturated fatty acid having one ormore electron withdrawing group associated with at least one double bondor a pharmaceutically acceptable salt thereof further including apharmaceutically acceptable carrier or excipient may be formulated as asolid, solution, powder, fluid emulsion, fluid suspension, semi-solid ordry powder.

Some embodiments of the invention are directed to a method for treatinga condition by administering an effective amount of an unsaturated orpolyunsaturated fatty acid having one or more electron withdrawing groupassociated with at least one double bond with the proviso that theelectron withdrawing group is not nitro (—NO₂) or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment. In suchembodiments, the one or more electron withdrawing group is selected fromaldehyde (—COH), acyl (—COR), carbonyl (—CO), carboxylic acid (—COOH),ester (—COOR), halides (—Cl, —F, —Br, —I), fluoromethyl (—CFO, allylfluoride (—CH═CHCH₂F), cyano (—CN), sulfoxide (—SOR), sulfonyl (—SO₂R),sulfonic acid (—SO₃H), and 1°, 2°, and 3° ammonium (—NR₃ ⁺), wherein Ris a hydrogen, methyl or C₂-C₆ alkyl. In some embodiments, theunsaturated or polyunsaturated fatty acid may include an aliphaticcarbon chain having from 12 to 18 carbons, and in other embodiments, theunsaturated or polyunsaturated fatty acid may be a ω-2, ω-3, ω-4, ω-5,ω-6, ω-7, ω-8, or ω-9 fatty acids and equivalents and derivativesthereof. For example in certain embodiments, the unsaturated orpolyunsaturated fatty acid may be linolenic acid, alpha-linolenic acid,eicosapentanoic acid, docosapentaenoic acid, docosahexaenoic acid,stearidonic acid, myristoleic acid, linoleic acid, gamma-linoleic acid,dihomo-gamma-linoleic acid, arachidonic acid, palmitoleic acid, oleicacid, erucic acid and equivalents and derivatives thereof.

In other embodiments, the one or more electron withdrawing group may bepositioned on an alpha carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid. In other embodiments, the oneor more electron withdrawing group may be positioned on a beta carbon ofa carbon-carbon double bond of the unsaturated or polyunsaturated fattyacid, and in still other embodiments, the one or more electronwithdrawing group may be positioned on a gamma carbon of a carbon-carbondouble bond of the unsaturated or polyunsaturated fatty acid. Inparticular embodiments, at least one of the one or more electronwithdrawing group may be an electron withdrawing vinyl group or anelectron withdrawing allylic group. In some embodiments, a carbon-carbondouble bond associated with the one or more electron withdrawing groupmay be in cis configuration, and in other embodiments, a carbon-carbondouble bond associated with the one or more electron withdrawing groupmay be in trans configuration. In certain embodiments, the effectiveamount may include a mixture of unsaturated or polyunsaturated fattyacids having one or more electron withdrawing group associated with atleast one double bond wherein the mixture includes electron withdrawinggroup positioned on alpha, beta, and gamma carbon of a carbon-carbondouble bonds of the unsaturated or polyunsaturated fatty acids.

In various embodiments, the condition may be, but may not be limited to,arterial stenosis, burns, hypertension, obesity, neurodegenerativedisorders, skin disorders, arthritis, autoimmune disease,autoinflammatory disease, lupus, Lyme's disease, gout, sepsis,hyperthermia, ulcers, enterocolitis, osteoporosis, viral or bacterialinfections, cytomegalovirus, periodontal disease, glomerulonephritis,sarcoidosis, lung disease, chronic lung injury, respiratory distress,lung inflammation, fibrosis of the lung, asthma, acquired respiratorydistress syndrome, tobacco induced lung disease, granuloma formation,fibrosis of the liver, graft vs. host disease, postsurgicalinflammation, coronary and peripheral vessel restenosis followingangioplasty, stent placement or bypass graft, acute and chronicleukemia, B lymphocyte leukemia, neoplastic diseases, arteriosclerosis,atherosclerosis, myocardial inflammation, psoriasis, immunodeficiency,disseminated intravascular coagulation, systemic sclerosis, amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, encephalomyelitis, edema, inflammatory bowel disease, hyper IgEsyndrome, cancer metastasis or growth, adoptive immune therapy,reperfusion syndrome, radiation burns, and alopecia.

Other embodiments of the invention are directed to a method for treatinga condition comprising administering an effective amount of anon-naturally occurring, unsaturated or polyunsaturated fatty acidhaving one or more electron withdrawing group or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment. In someembodiments, the non-naturally occurring, unsaturated or polyunsaturatedfatty acid may include an aliphatic chain having an odd number ofcarbons. For example in particular embodiments, the non-naturallyoccurring unsaturated or polyunsaturated fatty acid may include analiphatic chain having 5 to 23 carbons.

In some embodiments, the one or more electron withdrawing group mayinclude, but may not be limited to, aldehyde (—COH), acyl (—COR),carbonyl (—CO), carboxylic acid (—COOH), ester (—COOR), halides (—Cl,—F, —Br, —I), fluoromethyl (—CF_(n)), allyl fluoride (—CH═CHCH₂F), cyano(—CN), sulfoxide (—SOR), sulfonyl (—SO₂R), sulfonic acid (—SO₃H), and1°, 2° and 3° ammonium (—NR₃ ⁺), and nitro (—NO₂) wherein R is ahydrogen, methyl or C₂-C₆ alkyl. In certain embodiments, the one or moreelectron withdrawing group may be positioned on an alpha carbon of acarbon-carbon double bond of the unsaturated or polyunsaturated fattyacid. In other embodiments, the one or more electron withdrawing groupmay be positioned on a beta carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid, and in still otherembodiments, the one or more electron withdrawing group may bepositioned on a gamma carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid. In additional embodiments, atleast one of the one or more electron withdrawing group may be anelectron withdrawing vinyl group or an electron withdrawing allylicgroup.

In some embodiments, a carbon-carbon double bond associated with the oneor more electron withdrawing group may be in cis configuration, and inother embodiments, a carbon-carbon double bond associated with the oneor more electron withdrawing group may be in trans configuration. Incertain embodiments, the effective amount may include a mixture ofunsaturated or polyunsaturated fatty acids having one or more electronwithdrawing group associated with at least one double bond wherein themixture comprises electron withdrawing group positioned on alpha, beta,and gamma carbon of a carbon-carbon double bonds of the unsaturated orpolyunsaturated fatty acids.

In some embodiments, the condition may include, but may not be limitedto arterial stenosis, burns, hypertension, obesity, neurodegenerativedisorders, skin disorders, arthritis, autoimmune disease,autoinflammatory disease, lupus, Lyme's disease, gout, sepsis,hyperthermia, ulcers, enterocolitis, osteoporosis, viral or bacterialinfections, cytomegalovirus, periodontal disease, glomerulonephritis,sarcoidosis, lung disease, chronic lung injury, respiratory distress,lung inflammation, fibrosis of the lung, asthma, acquired respiratorydistress syndrome, tobacco induced lung disease, granuloma formation,fibrosis of the liver, graft vs. host disease, postsurgicalinflammation, coronary and peripheral vessel restenosis followingangioplasty, stent placement or bypass graft, acute and chronicleukemia, B lymphocyte leukemia, neoplastic diseases, arteriosclerosis,atherosclerosis, myocardial inflammation, psoriasis, immunodeficiency,disseminated intravascular coagulation, systemic sclerosis, amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, encephalomyelitis, edema, inflammatory bowel disease, hyper IgEsyndrome, cancer metastasis or growth, adoptive immune therapy,reperfusion syndrome, radiation burns, and alopecia.

Various embodiments of the invention are directed to a pharmaceuticalcomposition that may include any of the unsaturated or polyunsaturatedfatty acid or a non-naturally occurring, unsaturated or polyunsaturatedfatty acid or a pharmaceutically acceptable salt of either of thesedescribed herein and a pharmaceutically acceptable carrier or excipient.In some embodiments, such pharmaceutical compositions may furtherinclude one or more of diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,antioxidants, preservatives or combinations thereof. In otherembodiments, the pharmaceutical composition may be formulated as, forexample, a solid, solution, powder, fluid emulsion, fluid suspension,semi-solid or dry powder.

Yet other embodiments of the invention include methods for preparing anon-naturally occurring unsaturated or polyunsaturated fatty acid havingat least one electron withdrawing group including, for example, thesteps of contacting an unsaturated fatty acid with a mercuric salt and aselenium compound, contacting an intermediate resulting from the firststep with an electron withdrawing group donating reagent, and reactingthe intermediate resulting from the second step with an oxidizing agent.In some embodiments, the selenium compound may be, for example, PhSeBr,PhSeCl, PhSeO₂CCF₃, PhSeO₂H and PhSeCN, and in other embodiments, themercuric salt may be, for example, HgCl₂, Hg(NO₃)₂ and Hg(OAc)₂. Theelectron withdrawing group donating reagent of various embodiments maybe, for example, NaNO₂, AgNO₂ and HSO₂OH.

Still other embodiments of the invention are directed to methods forpreparing an unsaturated fatty acid having at least one electronwithdrawing group that may include the steps of combining a firstcomponent at least comprising an aliphatic hydrocarbon having anelectron withdrawing group at one end, a second component at leastcomprising aliphatic hydrocarbon chain having an aldehyde at one end,and a base to form a reaction mixture, generating a first intermediate,wherein the first intermediate comprises the first component covalentlybonded to the second component to form an alkane and wherein theelectron withdrawing group forms a first functional group and a hydroxylformed from the aldehyde forms a second functional group, and performinga dehydration on the first intermediate to generate an alkene. In someembodiments, the aliphatic hydrocarbon of the first component and thealiphatic hydrocarbon of the second component may be from 2 to 20carbons in length. In other embodiments, one of the first component orthe second component may further include an end group covalently bondedto the aliphatic hydrocarbon at the end opposite the electronwithdrawing group or the aldehyde, and wherein the functional group isnot an electron withdrawing group or an aldehyde. In still otherembodiments, the functional group may be, for example, carboxylic acid,carbohydrate, a phosphate, glycerol, and cholesterol ester, and in yetother embodiments, one of the first component or the second componentfurther include a functionalized reagent selected from phosphorousylide, phosphonate carbanion, α-silyl carbanion, phenyl sulfone,metallated heteroarylalkylsulfones, halide, or pseudohalide. The methodsof particular embodiments, and include the step of providing a catalystto the reaction mixture, the first intermediate or combination thereof,and in some embodiments, the catalyst may be a palladium catalyst. Invarious embodiments, the at least one electron withdrawing group may be,but may not be limited to, aldehyde (—COH), acyl (—COR), carbonyl (—CO),carboxylic acid (—COOH), ester (—COOR), halides (—Cl, —F, —Br, —I),fluoromethyl (—CF_(n)), cyano (—CN), sulfonyl (—SO₂R), sulfonic acid(—SO₃H), and 1°, 2° and 3° ammonium (—NR₃ ⁺), and nitro(—NO₂) wherein Ris a hydrogen, methyl or C₂-C₆ alkyl.

DESCRIPTION OF DRAWINGS

FIG. 1 illustrates the general synthetic method.

DETAILED DESCRIPTION

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.It is also to be understood that the terminology used in the descriptionis for the purpose of describing the particular versions or embodimentsonly, and is not intended to limit the scope of the present inventionwhich will be limited only by the appended claims. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art.Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the preferred methods, devices, and materialsare now described. All publications mentioned herein are incorporated byreference in their entirety. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a”, “an”, and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, reference toa “cell” is a reference to one or more cells and equivalents thereofknown to those skilled in the art, and so forth.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly into or onto a target tissue or toadminister a therapeutic to a patient, whereby the therapeuticpositively impacts the tissue to which it is targeted. Thus, as usedherein, the term “administering”, when used in conjunction with anitrated lipid can include, but is not limited to, providing a nitratedlipid to a subject systemically by, for example, intravenous injection,whereby the therapeutic reaches the target tissue. “Administering” acomposition may be accomplished by, for example, injection, oraladministration, topical administration, or by these methods incombination with other known techniques. Such combination techniquesinclude heating, radiation, ultrasound and the use of delivery agents.

The term “animal” as used herein includes, but is not limited to, humansand non-human vertebrates such as wild, domestic and farm animals.

The term “improves” is used to convey that the present invention changeseither the characteristics and/or the physical attributes of the tissueto which it is being provided, applied or administered. The term“improves” may also be used in conjunction with a diseased state suchthat when a diseased state is “improved” the symptoms or physicalcharacteristics associated with the diseased state are diminished,reduced or eliminated.

The term “inhibiting” includes the administration of a compound of thepresent invention to prevent the onset of the symptoms, alleviating thesymptoms, or eliminating the disease, condition or disorder.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

As used herein, the term “therapeutic” means an agent utilized to treat,combat, ameliorate, prevent or improve an unwanted condition or diseaseof a patient. In part, embodiments of the present invention are directedto the treatment of inflammation, obesity-related diseases, metabolicdiseases, cardiovascular diseases, cerebrovascular and neurodegenerativediseases, cancer or the aberrant proliferation of cells.

A “therapeutically effective amount” or “effective amount” of acomposition is a predetermined amount calculated to achieve the desiredeffect, i.e., to inhibit, block, or reverse the activation, migration,or proliferation of cells. The activity contemplated by the presentmethods includes both medical therapeutic and/or prophylactic treatment,as appropriate. The specific dose of a compound administered accordingto this invention to obtain therapeutic and/or prophylactic effectswill, of course, be determined by the particular circumstancessurrounding the case, including, for example, the compound administered,the route of administration, and the condition being treated. However,it will be understood that the effective amount administered will bedetermined by the physician in the light of the relevant circumstancesincluding the condition to be treated, the choice of compound to beadministered, and the chosen route of administration, and therefore, theabove dosage ranges are not intended to limit the scope of the inventionin any way. A therapeutically effective amount of compound of thisinvention is typically an amount such that when it is administered in aphysiologically tolerable excipient composition, it is sufficient toachieve an effective systemic concentration or local concentration inthe tissue.

The terms “treat,” “treated,” or “treating” as used herein refers toboth therapeutic treatment and prophylactic or preventative measures,wherein the object is to prevent or slow down (lessen) an undesiredphysiological condition, disorder or disease, or to obtain beneficial ordesired clinical results. For the purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationof symptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment.

Generally speaking, the term “tissue” refers to any aggregation ofsimilarly specialized cells which are united in the performance of aparticular function.

Embodiments of the invention presented herein are generally directed toactivated fatty acids and, in particular, activated unsaturated fattyacids. As used herein an “activated fatty acid” refers to a fatty acidhaving at least one electron withdrawing group covalently bound to acarbon of the saturated or unsaturated aliphatic chain of a fatty acid.Such activated fatty acids may be substituted by any number of electronwithdrawing groups at any number of positions on the hydrocarbon chainand such electron withdrawing groups may or may not be associated with acarbon-carbon double bond. Similarly, the activated fatty acidsdescribed herein may include any number of double bonds which may or maynot be associated with an electron withdrawing group. However, in thevarious embodiments of the invention, at least one double bond of anactivated fatty acid may be associated with an electron withdrawinggroup. In such embodiments, the electron withdrawing group may bepositioned in either cis or trans configuration at a double bond or ineither R or S absolute stereochemistry at an sp³ chiral/stereogeniccenter. For example, in one embodiment, an activated fatty acid may haveone electron withdrawing group, and in another, an activated fatty acidmay be substituted with multiple electron withdrawing groups at multiplepositions along the hydrocarbon chain. While the activated fatty acidsof the invention may have an electron withdrawing group positioned atany carbon along the aliphatic hydrocarbon chain between the carboxyterminal carbon to the terminal methyl (ω), in some embodiments, theelectron withdrawing group may be positioned within about 1 carbon fromthe carboxy terminal carbon and within about 1 carbon from the terminalmethyl. In other embodiments, the electron withdrawing group may bepositioned within about 3 carbons of either the carboxy terminal carbonand/or the methyl terminal carbon, and in still others embodiments, theelectron withdrawing group may be positioned within 5 carbons of eitherof the carboxy terminal carbon and/or the methyl terminal carbon.

In certain embodiments, the electron withdrawing group may be positionedon a carbon directly attached to a double bond of the activated fattyacid forming an “electron withdrawing vinyl” group. The electronwithdrawing group of such vinyl groups may be on either side of thedouble bond. Fatty acids encompassed by embodiments of the invention mayhave one or more than one electron withdrawing vinyl groups at anycarbon on the aliphatic hydrocarbon chain, and there are several waysthat an unsaturated fatty acid can have one electron-withdrawing group.In one embodiment, an activated oleic acid (ocatadecac-9-enoic acid)which is an 18 carbon, (0-6 fatty acid with one double bond (denoted“18:1”) between the 6^(th) (C-13) and 7^(th) (C-12) carbons, may have anelectron withdrawing group at either C-13 or C-12. In another exemplaryembodiment, an activated linoleic acid (octadeac-9,12,-dienoic acid),which is an 18 carbon, (0-6 fatty acid with two double bonds (denoted“18:2”) between the 6^(th) (C-13) and 7^(th) (C-12) carbons and the9^(th) (C-10) and 10^(th) (C-9) carbons, may have an electronwithdrawing group at C-9 or C-10 or C-12 or C-13. Similarly, otherpolyunsaturated fatty acids, with 3, 4, 5, 6 or more double bonds, canhave one electron withdrawing at either position on any of the doublebond carbons, including all possible permutations of positions andelectron-withdrawing groups.

In other embodiments, a mono or polyunsaturated fatty acid may have twoelectron-withdrawing groups, and there are several ways that anunsaturated fatty acid can have two electron-withdrawing groups. Forexample, in one embodiment, an activated oleic acid (ocatadecac-9-enoicacid), which is an 18 carbon, ω-6 fatty acid with one double bond(denoted “18:1”) between the 6^(th) (C-13) and 7^(th) (C-12) carbons,may have an electron withdrawing group at both C-13 and C-12. In anotherexemplary embodiment, an activated linoleic acid (octadeac-9,12,-dienoicacid), which is an 18 carbon, ω-6 fatty acid with two double bonds(denoted “18:2”) between the 6^(th) (C-13) and 7^(th) (C-12) carbons andthe 9^(th) (C-10) and 10^(th) (C-9) carbons, may have an electronwithdrawing group at any two of the positions C-9, C-10, C-12 or C-13,with the following possible permutations: C-9 and C-10, C-9 and C-12,C-9 and C-13, C-10 and C-12, C-10 and C-13, or C-12 and C-13.

In analogy to the preceding descriptions of compounds with oneelectron-withdrawing group or two electron-withdrawing groups, it isalso possible to have three, four, five or more electron withdrawinggroups. Following the same logic above, in the preceding descriptions ofcompounds with one electron-withdrawing group or twoelectron-withdrawing groups, polyunsaturated fatty acids, with 3, 4, 5,6 or more double bonds, can have multiple electron withdrawing (three,four, five or more, as available positions for substitution permit) atany of the positions on any of the double bond carbons, including allpossible permutations of positions and electron-withdrawing groups.Additionally, in any embodiments such as those described above, anynumber of non-electron-withdrawing groups may be covalently bound tocarbons of the aliphatic chain of the activated fatty acid. For example,in some embodiments, the activated fatty acids of the invention mayinclude one or more methyl, C₂-C₆ alkyl, alkenyl, or alkynyl or aminocovalently attached to one or more carbons of the aliphatic chain of anactivated fatty acid.

The term “electron-withdrawing group” is recognized in the art anddenotes the tendency of a substituent to attract valence electrons fromneighboring atoms, i.e., the substituent is electronegative with respectto neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (a)constant (see, e.g., J. March, Advanced Organic Chemistry, McGraw HillBook Company, New York, (1977 edition) pp. 251-259). The Hammettconstant values are generally negative for electron donating groups andpositive for electron withdrawing groups. For example the Hammetconstant for para substituted NH₂ (σ[P]) is about −0.7 and the σ[P] fora nitro group is about 0.8.

Embodiments of the invention encompass any known electron withdrawinggroup. For example, electron-withdrawing groups may include, but are notlimited to, aldehyde (—COH) acyl (—COR), carbonyl (—CO), carboxylic acid(—COOH), ester (—COOR), halides (—Cl, —F, —Br, etc.), fluoromethyl(—CFO, cyano (—CN), sulfonyl (—SO_(n)), sulfone (—SO₂R), sulfonic acid(—SO₃H), 1°, 2° and 3° ammonium (—NR₃ ⁺), and nitro(—NO₂) where each Rmay, independently, be hydrogen, methyl, or C₂ to C₆ alkyl, alkenyl, oralkynyl. In some embodiments, the electron withdrawing group may be astrong electron withdrawing group having a σ of at least about 0.2, andin certain embodiments, the electron withdrawing group may form adipole. For example, in particular embodiments, the electron withdrawinggroup may be a nitro, ammonium or sulfonyl. In other embodiments, theactivated fatty acids of the invention may be additionally substitutedby non-electron withdrawing groups or electron donating groupsincluding, for example, alcohol (—OH), reverse ester (—OOCR), alkyl,alkenyl, alkynyl, 1° and 2° amines (—NR₂), nitrate (—ONO₂), nitrito(—ONO) and the like.

The fatty acids of embodiments may be any unsaturated andpolyunsaturated fatty acid known in the art. The term “fatty acid”describes aliphatic monocarboxylic acids. Various embodiments includeactivated fatty acids having an aliphatic hydrocarbon chain identical orsimilar to identified, naturally occurring fatty acids. For example,aliphatic hydrocarbon chains of known naturally occurring fatty acidsare generally unbranched and contain an even number of from about 4 toabout 24 carbons, and others include fatty acids having from 12 to 18carbons in the aliphatic hydrocarbon chain. In still other embodiments,fatty acids may have greater than 24 carbons in the aliphatichydrocarbon chain. Embodiments of the invention encompass such naturallyoccurring fatty acids as well as non-naturally occurring fatty acids,which may contain an odd number of carbons and/or a non-naturallyoccurring linker. Thus, some embodiments of the invention include fattyacids having an odd number of carbons of, for example, from 5 to 23carbons, and in other embodiments, from 11 to 17 carbons. In yet otherembodiments, the fatty acids of embodiments may have greater than 23carbons. The naturally and non-naturally occurring fatty acids of theinvention may also be branched at one or more location along thehydrocarbon chain, and in various embodiments, each branch may includean aliphatic hydrocarbon chain of from 1 to 24 carbons, 2 to 20 carbonsor 4 to 18 carbons wherein each branch may have an even or odd number ofcarbons.

The aliphatic hydrocarbon chain of fatty acids of various embodimentsmay be unsaturated or polyunsaturated. The term “unsaturated” refers toa fatty acid having a aliphatic hydrocarbon chain that includes at leastone double bond and/or substituent. In contrast, a “saturated”hydrocarbon chain does not include any double bonds or substituents.Thus, each carbon of the hydrocarbon chain is ‘saturated’ and has themaximum number of hydrogens. “Polyunsaturated,” generally, refers tofatty acids having hydrocarbon chains with more than one double bond.The double bonds of the unsaturated or polyunsaturated fatty acids ofvarious embodiments may be at any location along the aliphatichydrocarbon chain and may be in either cis or trans configuration. Theterm “cis,” refers to a double bond in which carbons adjacent to thedouble bond are on the same side and the term “trans” refers to a doublebond in which carbons adjacent to the double bond are on opposite sides.Typically “cis” is the same as Z, and “trans” is the same as E butsometimes the IUPAC rules for naming compounds will give the opposite ofthis, which is the typical case in nitroalkenes. For example, anitroalkene can have the two carbon groups “cis” but the two groups thattake priority for the naming of compounds (a nitro group on one carbonof the alkene and a carbon group on the other carbon of the alkene) areon opposite sides and thus are E. Therefore the nitroalkene analog of a“cis” double bond is actually an E nitroalkene. Similarly, thenitroalkene analog of a “trans” double bond is actually a Z nitroalkene.Without wishing to be bound by theory, double bonds in cis configurationalong the carbon chain (cis carbon chain but E nitroalkene) may induce abend in the hydrocarbon chain. Double bonds in “trans,” configurationalong the carbon chain (trans carbon chain but Z nitroalkene) may notcause the hydrocarbon chain to bend. Embodiments of the invention mayinclude activated fatty acids having double bonds in either cis or transconfiguration, and encompass compositions that may include combinationsof cis and trans containing activated fatty acids and regioisomers ofthe activated fatty acids.

Many unsaturated and polyunsaturated fatty acids have been identifiedand are known to be naturally occurring. Such unsaturated orpolyunsaturated naturally occurring fatty acids, generally, include aneven number of carbons in their aliphatic hydrocarbon chain. Forexample, a naturally occurring unsaturated or polyunsaturated fatty acidmay have, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and so on carbons and mayinclude omega (ω)-3, ω-5, ω-6, ω-7, ω-9 fatty acids and the like. Anysuch fatty acid may be useful in embodiments of the invention. Thesymbol ‘ω’ is used to refer to the terminal methyl carbon of thealiphatic hydrocarbon chain. The placement of the double bond of the ω-Xfatty acid is the carbon-carbon bond X number of carbons from the ωcarbon. For example, an ω-6 fatty acid has a double bond between the6^(th) and 7^(th) carbons counting backward from the w carbon and an ω-3fatty acid has a double bond between the 3^(rd) and 4^(th) carbonscounting backward from the ω carbon. Various embodiments of theinvention include nitrated ω-3 fatty acids, including, but not limitedto, linolenic acid, alpha-linolenic acid, eicosapentanoic acid,docosapentaenoic acid, docosahexanoic acid and stearidonic acid;nitrated ω-5 fatty acids including, but not limited to, myristoleicacid; nitrated ω-6 fatty acids including, but not limited to, linoleicacid, gamma-linoleic acid, dihomo-gamma-linoleic acid and arachidonicacid; nitrated ω-7 fatty acids including, but not limited to,palmitoleic acid; and nitrated ω-9 fatty acids including, but notlimited to, oleic acid and erucic acid. Of course, the fatty acids ofthe invention may also be referred to using IUPAC nomenclature in whichthe placement of the double bond is determined by counting from thecarbon of the carboxylic acid, and ‘C—X’ denotes the carbon in aliphatichydrocarbons using IUPAC nomenclature wherein X is the number of thecarbon counting from the carboxylic acid. Embodiments of the inventionalso include synthetic equivalents to naturally occurring fatty acidsand derivatives thereof.

Other embodiments of the invention include unsaturated orpolyunsaturated non-naturally occurring fatty acids which may have anodd number of carbons such as, for example, 5, 7, 9, 11, 13, 15, 17, 19,20, 21 and so on. As in naturally occurring fatty acids, the one or moredouble bonds associated with non-naturally occurring fatty acids may beat any position along the aliphatic hydrocarbon chain, and the doublebonds may be in either cis or trans configuration. In yet otherembodiments, the non-naturally occurring fatty acids may include one ormore linker groups, which interrupt the aliphatic hydrocarbon chain. Forexample, in some embodiments, activated fatty acids may have one or morenon-carbon-carbon linkage such as, for example, ester, ether, vinylether, amino, imine and the like at any position within the aliphatichydrocarbon chain.

Various embodiments of the invention include unsaturated orpolyunsaturated fatty acids that may have a carbon-carbon double bondbetween any two carbons of the aliphatic chain of the fatty acid, andany number of carbon-carbon double bonds may be present in suchpolyunsaturated fatty acids. For example in some embodiments,polyunsaturated fatty acids may have 2, 3, 4, 5, 6 or more carbon-carbondouble bonds. In such embodiments, each of the more than onecarbon-carbon double bond may individually be in either cis or transconfiguration. In some embodiments, at least one of the carbon-carbondouble bonds of a polyunsaturated fatty acid may have an associatedelectron withdrawing group, and in other embodiments, more than one ofthe carbon-carbon double bonds of such polyunsaturated fatty acids mayhave an associated electron withdrawing group. Additionally, in suchembodiments, the electron withdrawing group may be associated witheither carbon of the carbon-carbon double bond or a carbon directlyadjacent to either carbon of the carbon-carbon double bond. For example,in some embodiments, an electron withdrawing group may be attached tothe alpha (α) carbon of the carbon-carbon double bond, and in otherembodiments, an electron withdrawing group may be associated with thebeta (β) carbon of the carbon-carbon double bond. In still otherembodiments, an electron withdrawing group may be associated with thegamma (γ) carbon, the carbon directly adjacent to, and attached to, acarbon-carbon double bond. In embodiments where a polyunsaturated fattyacid includes two or more carbon-carbon double bonds along the aliphaticchain and an electron withdrawing group is associated with any of thetwo or more carbon-carbon double bonds or each of the two or more of thecarbon-carbon double bonds, each electron withdrawing group may beattached to any carbon associated with each individual carbon-carbondouble bonds. For example, in some embodiments, an electron withdrawinggroup may be associated with each of the double bonds, with the electrongroup attached to either the (α) carbon, the beta (β) carbon or thegamma (γ) carbon of each double bond. In other embodiments, some of thedouble bonds can have an attached electron withdrawing group and some ofthe double bonds will not have attached electron withdrawing groups, andthose double bonds that do have attached electron withdrawing groups canhave electron withdrawing groups attached at either the (α) carbon, thebeta (β) carbon or the gamma (γ) carbon of each double bond.

In particular embodiments, an unsaturated fatty acid having at least oneelectron withdrawing group may be a conjugated fatty acid. In suchembodiments, two carbon-carbon double bonds in an aliphatic chain areadjacent to one another such that there is no methylene group betweenthem. Such conjugated compounds are commonly called 1,3-dienes, orconjugated fatty acids. Such 1,3-dienes may include one or more electronwithdrawing groups at any of 6 positions, at the 1, 2, 3, and/or 4positions of the 1,3-dienes and at the two carbons adjacent to the diene(at the 0 and 5 positions, in relation to the 1, 2, 3, 4 method ofidentifying carbons in a 1,3-diene). For example, one associatedelectron withdrawing group may be attached to any of the 6 positionsidentified above, that is to either the 1, 2, 3, or 4 positions on thediene or to either of the carbons adjacent to the 1,3-diene (at the 0 or5 positions, as described above). In additional embodiments, twoassociated electron withdrawing groups could be attached to any two ofthe six possible positions, three associated electron withdrawing groupscould be attached to any two of the six possible positions, fourassociated electron withdrawing groups could be attached to any two ofthe six possible positions, five associated electron withdrawing groupscould be attached to any two of the six possible positions, and sixassociated electron withdrawing groups could be attached to any two ofthe six possible positions. In summary, any configuration of electronwithdrawing groups attached to any of the six positions described abovein a 1,3-diene are encompassed by embodiments of the invention.

In certain embodiments, the activated fatty acids of the invention mayundergo an isomerization following preparation such that either thecis/trans configuration of the double bond, the location of the doublebond in the carbon chain, or both, may change. For example, in someembodiments, a activated fatty acid may be prepared with a carbon-carbondouble bond of having an electron withdrawing group attached to a gammacarbon of a carbon-carbon double bond. Following preparation, thecarbon-carbon double bond may undergo an isomerization such that theelectron withdrawing group is now conjugated with the carbon-carbondouble bond after isomerization. Such isomerizations may occurspontaneously at any time following preparation, and may result in acomposition which may have initially been prepared as including a singlespecies of activated fatty acid that subsequently includes a combinationof isomers of the first-prepared activated fatty acid originallyproduced. In other embodiments, an activated fatty acid may be preparedhaving an electron withdrawing group attached to a gamma carbon of acarbon-carbon double bond, and this carbon-carbon double bond mayundergo an isomerization following administration such that an activatedfatty acid is produced having the electron withdrawing group isconjugated with the carbon-carbon double bond.

In still other embodiments, the carboxy-terminal end of the activatedfatty acid may be modified. For example, in some embodiments, the fattyacid may include a glycerol associated with the carboxy-terminal end ofthe fatty acid to create a glycerolipid, and such glycerolipids may bemono-, di-, or tri-glycerides wherein at least one of the fatty acids ofa di- or tri-glyceride may be an activated fatty acid and any remainingfatty acids may be a saturated or unsaturated fatty acid. Similarly, inother embodiments, a carbohydrate may be associated with thecarboxy-terminal end of an activated fatty acid to form a glycolipid. Insuch embodiments, any carbohydrate known in the art may be acarbohydrate moiety of a glycolipid including, but not limited to,galactose and glucose. In yet other embodiments, a carbohydrate may beassociated with a glyceride which is associated with thecarboxy-terminal end of an activated fatty acid to form aglycero-glycolipid, which may have one or two activated fatty acidsassociated with the glycero-portion of the glycero-glycolipid and, inembodiments in which only one activated fatty acid is associated withthe glycero-glycolipid, the remaining position on the glycerol mayinclude a saturated or unsaturated fatty acid or hydrogen, alkyl, or afunctional group such as, for example, alcohol, amine, phosphate,phosphonic acid, thiol, sulfonic acid and the like. In certainembodiments, the carboxy-terminal end of the activated fatty acids ofthe invention may be associated with a phosphate to from a phospholipid.In such embodiments, the phosphate may be directly associated with thefatty acid through the carboxy-terminus, or the phosphate may beassociated with a di-glyceride wherein one or two activated fatty acidsare attached glycerol moiety and, in embodiments where only oneactivated the fatty acid is attached to the glycerol, remaining positionon the glycerol may include a saturated or unsaturated fatty acid orhydrogen, alkyl, or a functional group such as, for example, alcohol,amine, phosphate, phosphonic acid, thiol, sulfonic acid and the like. Infurther embodiments, the carboxy-terminus of the activated fatty acidmay be associated with a cholesterol or other sterol moiety. In yetother embodiments, the carboxy-terminal end may be modified by thecovalent attachment of a secondary active agent. In the particularembodiments, carboxy-terminal modifications including a glycerol may notinclude a nitro group. Without wishing to be bound by theory,modification of the carboxy-terminal end of activated fatty acids mayenhance partitioning of the activated fatty acid after administrationand may also improve resilience of the activated fatty acid byinhibiting beta-oxidation in mitochondria following administration.

For example, embodiments of the invention include compounds of generalformulae I and II:

wherein R₁ and R₂ are independently selected from —H and any electronwithdrawing groups including, but not limited to —COH, —COR, —CO, —COOH,—COOR, —Cl, —F, —Br, —I, —CF₃, —CN, —SO₃ ⁻, —SO₂R, —SO₃H, —NH₃ ⁺,—NH₂R⁺, —NHR₂ ⁺, —NR₃ ⁺ and —NO₂ ⁻ wherein at least one of R₁ and R₂ isan electron withdrawing group and m and n are, independently, 1-20. Someembodiments include compounds of general formula III:

wherein R₁, R₂, m and n are as described above, R₃ and R₄ are,independently, selected from —H, —COH, —COR, —CO, —COOH, —COOR, —Cl, —F,—Br, —I, —CF₃, —CN, —SO₃ ⁻, —SO₂R, —SO₃H, —NH₃ ⁺, —NH₂R⁺, —NHR₂ ⁺, —NR₃⁺ and —NO₂ ⁻, k and p are, independently, 0 to 5 and x and y areindependently, 0 to 3, and wherein each double bond is in either cis ortrans configuration. In still other embodiments, any carbon associatedwith m, n, k or p may be substituted.

Compounds encompassed by the formulae described above include, but arenot limited to, (E)-9-nitro-octadec-9-enoic acid,(E)-10-nitro-octadec-9-enoic acid, (E)-8-nitro-octadec-9-enoic acid,(E)-11-nitro-octadec-9-enoic acid, (E)-10-acetyltetradec-9-enoic acid,(E)-9-acetyltetradec-9-enoic acid, (E)-11-acetyltetradec-9-enoic acid,(E)-8-acetyltetradec-9-enoic acid, (E)-13-chloro-docosen-13-enoic acid,(E)-14-chloro-docosen-13-enoic acid, (E)-12-chloro-docosen-13-enoicacid, (E)-15-chloro-docosen-13-enoic acid,(E)-10-methylsulfonylhexadec-9-enoic acid,(E)-9-methylsulfonylhexadec-9-enoic acid,(E)-11-methylsulfonylhexadec-9-enoic acid, and(E)-8-methylsulfonylhexadec-9-enoic acid. Other embodiments include theZ-isomer of such compounds. Further embodiments include, for example,(E)-9-nitro-pentadec-9-enoic acid, (E)-10-nitro-pentadec-9-enoic acid,(E)-8-nitro-pentadec-9-enoic acid, (E)-11-nitro-pentadec-9-enoic acid,(E)-10-acetylheptadec-9-enoic acid, (E)-9-acetylheptadec-9-enoic acid,(E)-11-acetyloctahepta-9-enoic acid, (E)-8-acetylheptadec-9-enoic acid,(E)-10-chloro-pentadec-9-enoic acid, (E)-9-chloro-pentadec-9-enoic acid,(E)-11-chloro-pentadec-9-enoic acid, (E)-8-chloro-pentadec-9-enoic acid,(E)-10-methylsulfonylnonadec-9-enoic acid,(E)-9-methylsulfonylnonadec-9-enoic acid,(E)-11-methylsulfonylnonadec-9-enoic acid,(E)-8-methylsulfonylnonadec-9-enoic acid, and the (Z)-isomers thereof.Yet other embodiments include, for example,E)-9-nitro-eicos-11,14-ienoic acid, (E)-10-nitro-eicos-8,13-ienoic acid,(E)-8-nitro-eicos-11,14-ienoic acid, (E)-11-nitro-eicos-8,13-ienoicacid, (E)-10-acetylnonadec-10,13-ienoic acid,(E)-9-acetylnonadec-9,12-enoic acid, (E)-11-acetylnonadec-10,13-ienoicacid, (E)-8-acetylnonadec-9,12-enoic acid,(E)-10-chloro-heptadec-9,11-ienoic acid,(E)-9-chloro-hetpadec-10,12-ienoic acid,(E)-11-chloro-heptadec-9,11-ienoic acid,(E)-8-chloro-heptadec-10,11-ienoic acid,(E)-10-methylsulfonylpentadec-9,11-ienoic acid,(E)-9-methylsulfonylpentadec-8,9-ienoic acid,(E)-11-methylsulfonylpentadec-9,10-ienoic acid, and(E)-8-methylsulfonylpentadec-8,9-ienoic acid, and (Z)-isomers thereof.As indicated by the list above, fatty acids of any length with anynumber of carbon-carbon double bonds are any position along thealiphatic chain can be prepared and are encompassed by the invention.

The activated fatty acids described above may be prepared as apharmaceutically acceptable formulation. The term “pharmaceuticallyacceptable” is used herein to mean that the compound is appropriate foruse in a pharmaceutical product. For example, pharmaceuticallyacceptable cations include metallic ions and organic ions. Morepreferred metallic ions include, but are not limited to, appropriatealkali metal salts, alkaline earth metal salts and other physiologicalacceptable metal ions. Exemplary ions include aluminum, calcium,lithium, magnesium, potassium, sodium and zinc in their usual valences.Preferred organic ions include protonated tertiary amines and quaternaryammonium cations, including in part, trimethylamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Exemplarypharmaceutically acceptable acids include, without limitation,hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaricacid, maleic acid, malic acid, citric acid, isocitric acid, succinicacid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid,oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamicacid, benzoic acid, and the like.

Isomeric and tautomeric forms of activated fatty acids of the inventionas well as pharmaceutically acceptable salts of these compounds are alsoencompassed by the invention. Exemplary pharmaceutically acceptablesalts are prepared from formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, .beta.-hydroxybutyric, galactaric andgalacturonic acids.

Suitable pharmaceutically acceptable base addition salts used inconnection with the activated fatty acids of the invention includemetallic ion salts and organic ion salts. Exemplary metallic ion saltsinclude, but are not limited to, appropriate alkali metal (group Ia)salts, alkaline earth metal (group IIa) salts and other physiologicalacceptable metal ions. Such salts can be made from the ions of aluminum,calcium, lithium, magnesium, potassium, sodium and zinc. Preferredorganic salts can be made from tertiary amines and quaternary ammoniumsalts, including in part, trimethylamine, diethylamine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All of theabove salts can be prepared by those skilled in the art by conventionalmeans from the corresponding compound of the present invention.

Activated fatty acids as described in various embodiments of theinvention above, may be administered to individuals to treat, ameliorateand/or prevent a number both acute and chronic inflammatory andmetabolic conditions. In particular embodiments, activated fatty acidsmay be used to treat acute conditions including general inflammation,autoimmune disease, autoinflammatory disease, arterial stenosis, organtransplant rejection and burns, and chronic conditions such as, chroniclung injury and respiratory distress, diabetes, hypertension, obesity,arthritis, neurodegenerative disorders and various skin disorders.However, in other embodiments, activated fatty acids may be used totreat any condition having symptoms including chronic or acuteinflammation, such as, for example, arthritis, lupus, Lyme's disease,gout, sepsis, hyperthermia, ulcers, enterocolitis, osteoporosis, viralor bacterial infections, cytomegalovirus, periodontal disease,glomerulonephritis, sarcoidosis, lung disease, lung inflammation,fibrosis of the lung, asthma, acquired respiratory distress syndrome,tobacco induced lung disease, granuloma formation, fibrosis of theliver, graft vs. host disease, postsurgical inflammation, coronary andperipheral vessel restenosis following angioplasty, stent placement orbypass graft, coronary artery bypass graft (CABG), acute and chronicleukemia, B lymphocyte leukemia, neoplastic diseases, arteriosclerosis,atherosclerosis, myocardial inflammation, psoriasis, immunodeficiency,disseminated intravascular coagulation, systemic sclerosis, amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, encephalomyelitis, edema, inflammatory bowel disease, hyper IgEsyndrome, cancer metastasis or growth, adoptive immune therapy,reperfusion syndrome, radiation burns, alopecia and the like.

When administered, activated fatty acids may interact with a number ofcellular receptors and/or proteins that mediate inflammation, either byinhibiting or stimulating their activity thereby inhibiting or reducinginflammation. Without wishing to be bound by theory, activated fattyacids may modulate important signaling activities including, forexample, neurotransmission, gene expression, vascular function andinflammatory responses, and chemical properties of activated fatty acidsthat may facilitate these activities include, but are not limited to,the strong, reversible electrophilic nature of the β carbon adjacent tothe electron withdrawing vinyl group, an ability to undergo Nef-likeacid base reactions to release NO, an ability to partition into bothhydrophobic and hydrophilic compartments, and a strong affinity forG-protein coupled receptors and nuclear receptors.

For example, in one embodiment, activated fatty acids may beadministered to mediate cell signaling via multiple G-protein coupledreceptors and nuclear receptors such as, but not limited to, peroxisomeproliferator-activated receptors (PPAR) including PPARα, PPARγ, andPPARδ. PPAR is a nuclear receptor that is expressed throughout anorganism, including in monocytes/macrophages, neutrophils, endothelialcells, adipocytes, epithelial cells, hepatocytes, mesangial cells,vascular smooth muscle cells, neuronal cells and when “activated”induces transcription of a number of target genes. Activation of PPARhas been shown to play various roles in regulating tissue homeostasisincluding, for example, increasing insulin sensitivity, suppress chronicinflammatory processes, reduce circulating free fatty acid levels,correct endothelial dysfunction, reduce fatty streak formation, delayplaque formation, limit blood vessel wall thickening and enhance plaquestabilization and regression. The activated fatty acids embodied hereinmay perform each of these functions associated with PPAR activation.

Moreover, activated fatty acids may perform these functions withoutsignificantly altering normal cellular process. For example, in oneembodiment, an activated fatty acid may be administered to treathypertension by lowering blood pressure to normal levels withoutreducing the blood pressure of the individual below normal levels evenif the activated fatty acid is over-administered. Thus, without wishingto be bound by theory, the activated fatty acids of the invention mayprovide treatment of an individual without the negative affectsassociated with over-administration or over-treatment using traditionalmedications.

Activation of PPAR has been shown to be induced either directly or inpart by a locking reaction in which a critical thiol in a highlyconserved cysteine (Cys 285 of human PPARγ) which is located in a ligandbinding domain of PPAR. Partial activation of PPAR has been shown tooccur when relatively high concentrations of known thiol reactivecompounds, such as 15-deoxy-Δ^(12,14)-prostaglandin J₂ (15-d PGJ₂), areadministered. Without wishing to be bound by theory, activated fattyacids may bind to PPAR covalently at the reactive thiol in the ligandbinding domain of PPAR. Moreover, activated fatty acids may induce aconformational change in PPAR. More specifically, activated fatty acidbinding may result in the C-terminus of the ligand binding domain(α-helix 12) to adopt an active conformation that may promote abeneficial pattern of co-repressor release and co-activator recruitment.Thus, activated fatty acids may enhance PPAR activation andtranscription of PPAR regulated genes beyond that of known PPARactivating compounds.

In addition to activation of PPAR, activated fatty acid administrationmay be useful for activating a number of other factors important forcell signaling. For example, in one embodiment, activated fatty acidsmay be administered to induce gene expression and tissue activity ofheme oxygenase-1 (HO-1) which has been shown to mediate adaptive andprotective responses during inflammation, and activation of an adaptiveor protective inflammatory response mediated by HO may be useful intreating inflammatory diseases such as, but not limited to,atheroscelrosis, acute renal failure, vascular restinosis, transplantrejection, and sepsis. In another embodiment, activated fatty acids mayinduce a reversible post-translational modification of proteins, suchas, for example, glutathione (GSH) and glyceraldehyde-3-phosphatedehydrogenase (GAPDH) by covalently binding to catalytic cysteines onsuch proteins. Without wishing to be bound by theory, the covelentmodification of these proteins by activated fatty acids may increase thehydrophobicity of these proteins inducing translocation of to membranesand suggests a role for redox regulation of enzyme function, cellsignaling and protein trafficking. In yet another embodiment, activatedfatty acids may be administered to repress NF-κB dependent geneexpression and endothelial tumor necrosis factor-α induced expression ofvascular cell adhesion molecules in monocytes and macrophages whichresults in inhibition of rolling and adhesion during inflammation. Thus,activated fatty acids may be useful for treating general inflammationresulting from surgery, injury or infection. In a further embodiment,activated fatty acids may be administered to limit tissue inflammatoryinjury and inhibit the proliferation of vascular smooth muscle cells byincreasing cellular levels of nuclear factor erythroid 2-relatedfactor-2 (Nrf-2) which may be useful in the treatment of a number ofvascular diseases. In some embodiments, activated fatty acids may beadministered to modify the activity of transient receptor potential(TRP) channels such as TRPA1 and TRPV1 and may be capable of modifyingpain and inflammatory signaling. In other embodiments, activated fattyacids may be used to induce heat shock factor (HSF) proteins and inhibitprotein tyrosine phosphatases (PTPs), and in still other embodiments,activated fatty acids may be administered to activate mitogen-activatedprotein kinases (MAP kinases).

In a still further embodiment, activated fatty acids may be useful forischemic preconditioning. For example, nitrated fatty acids produced bymitochondria in cells under ischemic conditions cause a number ofphysiological changes within the cell that increases cell survival underischemic conditions. By providing activated fatty acids to anindividual, similar ischemic preconditioning may be achieved allowingfor improved survival of, for example, cardiac tissue under ischemicconditions or organs being preserved for optimizing viability andfunction upon transplantation.

The activated fatty acids of the invention can be administered in anyconventional manner by any route where they are active. Administrationcan be systemic or local. For example, administration can be, but is notlimited to, parenteral, subcutaneous, intravenous, intramuscular,intraperitoneal, transdermal, oral, buccal, or ocular routes, orintravaginally, by inhalation, by depot injections, or by implants. Incertain embodiments, the administration may be parenteral orintravenous, all in the presence or absence of stabilizing additivesthat favor extended systemic uptake, tissue half-life and intracellulardelivery. Thus, modes of administration for the compounds of the presentinvention (either alone or in combination with other pharmaceuticals)can be injectable (including short-acting, depot, implant and pelletforms injected subcutaneously or intramuscularly). In some embodiments,an injectable formulation including an activated fatty acid may bedeposited to a site of injury or inflammation, such as, for example, thesite of a surgical incision or a site of inflammation due toarthroscopy, angioplasty, stent placement, by-pass surgery and so on.

In certain other embodiments, the compounds of the invention may beapplied locally as a salve or lotion applied directly to an area ofinflammation. For example, in some embodiments, a lotion or salveincluding activated fatty acids of the invention may be prepared andapplied to a burn, radiation burn, site of dermal disorder, edema,arthritic joint or the like.

Various embodiments, of the invention are also directed to method foradministering activated fatty acids. Specific modes of administrationmay vary and may depend on the indication. The selection of the specificroute of administration and the dose regimen may be adjusted or titratedby the clinician according to methods known to the clinician in order toobtain the optimal clinical response. The amount of compound to beadministered is that amount which is therapeutically effective. Thedosage to be administered will depend on the characteristics of thesubject being treated, e.g., the particular animal treated, age, weight,health, types of concurrent treatment, if any, and frequency oftreatments, and can be easily determined by one of skill in the art(e.g., by the clinician). Those skilled in the art will appreciate thatdosages may be determined with guidance, for example, from Goodman &Goldman's The Pharmacological Basis of Therapeutics, Ninth Edition(1996), Appendix II, pp. 1707-1711 or from Goodman & Goldman's ThePharmacological Basis of Therapeutics, Tenth Edition (2001), AppendixII, pp. 475-493 both of which are hereby incorporated by reference intheir entireties. With respect to conventional prenylation enzymeinhibitors, guidance may be obtained from art-recognized dosage amountsas described, for example, by J. E. Karp, et al., Blood,97(11):3361-3369 (2001) and A. A. Adjei, et al., Cancer Research,60:1871-1877 (2000) hereby incorporated by reference in its entirety.

In various embodiments, an effective amount of an activated fatty aciddelivered during each administration cycle may range from about 10mg/m²/day to about 1000 mg/m²/day. In some embodiments, an effectiveamount may be about 20 mg/m²/day to about 700 mg/m²/day, and in others,an effective amount may be about 30 mg/m²/day to about 600 mg/m²/day. Inparticular embodiments, an effective amount may be about 50 mg/m²/day,about 400 mg/m²/day, about 500 mg/m²/day, or about 600 mg/m²/day. In yetother embodiments, an effective amount of an activated fatty acid mayvary as treatment progresses. For example, a dosage regimen may beincreased or decreased as treatment proceeds through administrationcycles, or the daily dosage may increase or decrease throughoutadministration. In additional embodiments, greater than 1000 mg/m²/daymay be administered because even high doses of activated fatty acid aregenerally tolerable to the patient and may not produce undesiredphysiological effects.

In some embodiments, the dosage regimen as described above may becombined with a secondary form of treatment or a secondary agent

The activated fatty acids of various embodiments may be prepared by anymethod known in the art. For example, in one embodiment, an activatedfatty acid may be prepared by:

-   -   i) contacting an unsaturated fatty acid with a mercuric salt and        a selenium compound;    -   ii) contacting the intermediate resulting from step a) with a        reagent or reactant that can introduce an electron withdrawing        group; and    -   iii) reacting the intermediate resulting from step b) with an        oxidizing agent.

Without wishing to be bound by theory, a selenium compound, such as, forexample, PhSeBr, PhSeCl, PhSeO₂CCF₃, PhSeO₂H, PhSeCN and the like, mayreact with one or more carbon-carbon double bond of the unsaturatedfatty acid to form a three-membered ring intermediate on the fatty acidin a reaction that may be facilitated by the mercuric salt such as, forexample, HgCl₂, Hg(NO₃)₂, Hg(OAc)₂ and the like as depicted in step I ofthe reaction below:

The source of the electron withdrawing group may be any compound knownin the art that is capable of generating an electron withdrawing groupthat can be incorporated into the activated fatty acid, such as, forexample, NaNO₂, AgNO₂, HSO₂OH, and the like. Without wishing to be boundby theory, the electron withdrawing group (X in the reaction schemeabove) may become joined to the hydrocarbon chain by displacing, forexample, the bromine that was associated with the selenium compound asdepicted in step 11 of the reaction scheme provided above. It is notedthat the electron withdrawing groups may also react directly with thethree-membered ring episelenonium ion shown in step I at the positionwhere the bromine is shown as attacking. Finally, as depicted in stepIII of the reaction scheme provided above, the oxidizing agent forms areactive selenium-oxo functional group, which undergo molecularrearrangement and elimination of ZSeOH leading to formation of theelectron withdrawing vinyl (depicted as a nitro vinyl) on thehydrocarbon chain. Z in the reaction scheme above may be any number ofgroups. For example, in certain embodiments, Z may be a phenyl group.

In other embodiments, an activated fatty acid may be prepared using amodified aldol condensation such as the Henry reaction. A review of theHenry reaction and methods related to the Henry method can be found, forexample, in Frederick A. Luzzio, F. A. “The Henry reaction: recentexamples” Tetrahedron 2001, 57, 915-945 which is hereby incorporated byreference in its entirety. Known variations of the Henry reaction mayalso be useful in preparing activated fatty acids and all such methodsare embodied herein. For example, in some embodiments, variations of theHenry reaction including, but not limited to, the Wittig-like variationof the Henry reaction, the Horner-Wadsworth-Emmons variation of theHenry reaction, and the Peterson-olefination variation of the Henryreaction. In such methods, double bonds are formed using the assistanceof groups temporarily included in the reactants but that do are notincluded in the product. For example, the Wittig reaction usesphosphorus ylides to aid in the condensation reactions with carbonylsand in the dehydration reaction to form alkenes. TheHorner-Wadsworth-Emmons reaction uses phosphonate esters, and thePeterson olefination uses silicon reagents for the condensation anddehydration steps. A review of major alkene-forming name reactions byreaction of a functionalized reagent with a carbonyl compound includingthe Wittig reaction, Horner-Wittig, Horner-Wadsworth-Emmons can befound, for example, in Peterson, Johnson, and Julia reactions.Blakemore, P. R. “The modified Julia olefination: alkene synthesis viathe condensation of metallated heteroarylalkylsulfones with carbonylcompounds J. Chem. Soc., Perkin Trans. 1, 2002, 2563-2585 which ishereby incorporated by reference in its entirety.

The Henry “nitro-aldol” reaction is the condensation of a nitroalkanewith either an aldehyde or a ketone carbonyl containing compound to forma nitro-aldo product with the newly-formed beta-hydroxynitroalkyl group.Dehydration (loss of water) from nitro-aldol products leads to theformation of nitroalkenes. There are many methods to perform thenitroalkane-carbonyl condensation reaction to make nitro-aldols andthere are many methods for the dehydration reaction to formnitroalkenes. Examples of such methods can be found in, for example,Woodcock, S. R.; Marwitz, A. J. V. Bruno, P.; Branchaud, B. P.“Synthesis of Nitrolipids. All Four Possible Diastereomers of NitrooleicAcids: (E)- and (Z)-, 9- and 10-Nitro-octadec-9-enoic Acids” OrganicLetters, 2006, 8, 3931-3934 which provides one regioisomer and usuallyone of two possible alkene cis/trans or Z/E diastereomers, in highpurity and usually in high chemical yield, which is hereby incorporatedby reference in its entireties.

Enantioselective Henry reactions are also possible and may require theuse of one or more catalysts for the reaction, and embodiments of theinvention, include the use of such methods to prepare stereospecificisomers of nitroalkenes. For example, Boruwa, J.; Gogoi, N.; Saikia, P.P.; and Barua, N. C. “Catalytic Asymmetric Henry Reaction” Tetrahedron:Asymmetry 2006, 17, 3315-3326 which is hereby incorporated by referencein its entirety, describes methods for preparing stereospecific isomersof nitoralkenes.

In still other embodiments, alkenes (olefins) may be prepared bymetal-mediated cross coupling reactions (joining together of twomolecules to make one new molecule) by condensation onto a carbonylcompound. Such methods have not been applied to the formation ofnitroalkenes or to the formation of other alkenes withelectron-withdrawing substituents, but such methods could be adapted tothe synthesis of alkenes with electron-withdrawing substituents. Forexample, named cross coupling reactions such as the Heck, Suzuki andStille coupling, along with others may be used to prepare activatedfatty acids. Such methods are well known in the art. A review of suchreactions of can be found in, for example, Metal-CatalyzedCross-Coupling Reactions de Meijere, Armin/Diederich, Françcois (eds.)Wiley-VCH, Weinheim 2004. XXII, ISBN-10: 3-527-30518-1 and ISBN-13:978-3-527-30518-6 which are hereby incorporated by reference in theirentireties.

Examples of various embodiments of methods for preparing activated fattyacids may at least include the following steps:

-   -   i) combining a first component at least including an aliphatic        hydrocarbon having an electron withdrawing group at one end with        an second component including aliphatic hydrocarbon chain having        an aldehyde at one end in the presence of a base to form a first        intermediate; and    -   ii) generating an alkene from the first intermediate.        Exemplary reactions are presented in schemes I and II below:

In reaction schemes I and II, the variable X represents an electronwithdrawing group and can be any electron withdrawing group discussedherein above or known in the art. The variables n and m represent anumber of carbon atoms in the aliphatic hydrocarbon chain, and n and mcan be any number. For example, the aliphatic hydrocarbon chains of anyof the starting compound may be from 2-20 carbons in length. Moreover,the position of the double bond and the arrangement of the electronwithdrawing group in relation to the double bond may be determinedspecifically, and particular activated fatty acids may be created inhigh yield. For example, an oleic acid may be produced by the reactionof scheme I by combining a first substrate where m is 10 and a secondsubstrate where n is 2.

Any activated fatty acid may be produced using the method presentedabove, and both naturally-occurring and non-naturally-occurring analogsmay be synthesized. For example, synthesis of an exemplary nitratedfatty acids may be produced as illustrated in the general syntheticmethod is shown in FIG. 1.

In such embodiments, R₁ and R₂ can include any number of carbons. Forexample in one embodiment, a naturally occurring fatty acid having aneven number of carbons (20 carbons total, in this case) may be preparedfrom components where R₂ is CH₂CH₃ and R₁ is (CH₂)₁₅CO₂R₃, where R₃ is aprotecting group for the carboxylic acid functional group found in fattyacids. Similarly, a non-naturally occurring fatty acid having an oddnumber of carbons (19 carbons total, in this case) may be prepared fromcomponents where R₂ is CH₂CH₃ and R₁ is (CH₂)₁₄CO₂R₃, where R₃ is aprotecting group for the carboxylic acid functional group found in fattyacids. The method illustrated in scheme III can be applied to thesynthesis of essentially any nitrated lipid having either an even or anodd number of carbons by incorporating different R₁ and R₂ groups. Forexample, each of R₁ and R₂ may be an aliphatic or substituted aliphaticcarbon chain having from 1 to 20 carbons, although any greater number ofcarbons is also possible. Moreover, individual R₁ and/or R₂ groups mayinclude any number of carbon-carbon double bonds, which may or may notinclude associated electron withdrawing groups attached to an alpha,beta, or gamma carbon of the carbon-carbon double bond. Similarly,individual R₁ and R₂ groups may include branched chains. In suchembodiments, the additional carbon-carbon double bonds associated withR₁ and/or R₂ may be conjugated, unconjugated, or partially conjugatedwith one another or will become conjugated with a carbon-carbon doublebond created as a result of the reaction. As indicated above, thereaction depicted in scheme III may be carried out sequentially tocreate an activated fatty acid having more than one carbon-carbon doublebond with associated electron withdrawing groups. In such embodiments,individual R₁ and R₂ groups for each reaction in a sequence may be from1 to about 12 carbons, although any greater number of carbons is alsopossible.

In some embodiments, individual R₁ and R₂ groups may contain additionalfunctional groups other than double bonds, which may or may not beassociated with a carbon-carbon double bond either existing before thereaction is carried out or following the reaction illustrated in SchemeIII. For example, individual R₁ and R₂ groups may include functionalgroups such as, but not limited to, alkynes, as a part of the chain,with the alkyne in the chain, alcohols, aldehyde carbonyls, ketonecarbonyls, derivatives of carbonyl aldehydes and ketones, such as,oximes, hydrazones and any other carbonyl derivative known in the art,amines, amines with other groups known in the art attached to the amine,thiols, thiols with other groups known in the art attached to thethiols, any other functional group known in the art, either as thesimple functional group or the functional group with another chain orgroup attached to it. Such functional groups may be attached to a carbonin the linear or branched chain. Without wishing to be bound by theory,the addition of additional functional groups may alter the targeting andbioavailability of the activated fatty acids of embodiments, such thatspecific cells or targets it within cells can be targeted.

In yet other embodiments, molecules may contain more than one carbonchain, with two or more carbon chains joined together by a non-carbongroup, and in some embodiments, each of the carbon chains can bebranched or linear. For example, in certain embodiments, non-carbonfunctional groups that can join two or more carbon chains togetherinclude, but are not limited to, those in the very common functionalgroups listed below:

-   -   Ethers R₁—O—R₂,    -   Amines R₁—NR₃—R₂,    -   Esters R₁—C(═O)—O—R₂,    -   Amides R₁—C(═O)—NR₃—R₂    -   ThioEsters R₁—C(═S)—O—R₂ or R₁—C(═O)—S—R₂    -   ThioAmides R₁—C(═S)—NR₃—R₂        In addition to the common non-carbon multivalent elements found        in organics compounds and shown above (oxygen, nitrogen &        sulfur), other functional groups known in the art, and based on        any other non-carbon multivalent element may be used in        embodiments of the invention. In various embodiments, any of the        non-carbon chains described above could be incorporated into        activated fatty acids using the general synthetic approach shown        in III, above, in which the non-carbon chains are in R₁, R₂ or        both.

Pharmaceutical formulations containing the compounds of the inventionand a suitable carrier can be in various forms including, but notlimited to, solids, solutions, powders, fluid emulsions, fluidsuspensions, semi-solids, and dry powders including an effective amountof an activated fatty acid of the invention. It is also known in the artthat the active ingredients can be contained in such formulations withpharmaceutically acceptable diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,antioxidants, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's, The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) both of which are herebyincorporated by reference in their entireties can be consulted.

The compounds of the present invention can be formulated for parenteralor intravenous administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection can be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions can take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and can containformulatory agents such as suspending, stabilizing and/or dispersingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids diluents such as oleic acid finduse in the preparation of injectables. Additional fatty acids diluentsthat may be useful in embodiments of the invention include, for example,one or more of stearic acid, metallic stearate, sodium stearyl fumarate,fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineraloil, vegetable oil, paraffin, leucine, silica, silicic acid, talc,propylene glycol fatty acid ester, polyethoxylated castor oil,polyethylene glycol, polypropylene glycol, polyalkylene glycol,polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcoholether, polyethoxylated sterol, polyethoxylated castor oil,polyethoxylated vegetable oil, and the like. In some embodiments, thefatty acid diluent may be a mixture of fatty acids. In some embodiments,the fatty acid may be a fatty acid ester, a sugar ester of fatty acid, aglyceride of fatty acid, or an ethoxylated fatty acid ester, and inother embodiments, the fatty acid diluent may be a fatty alcohol suchas, for example, stearyl alcohol, lauryl alcohol, palmityl alcohol,palmitolyl acid, cetyl alcohol, capryl alcohol, caprylyl alcohol, oleylalcohol, linolenyl alcohol, arachidonic alcohol, behenyl alcohol,isobehenyl alcohol, selachyl alcohol, chimyl alcohol, and linoleylalcohol and the like and mixtures thereof.

Other embodiments of the invention include activated fatty acid preparedas described above which are formulated as a solid dosage form for oraladministration including capsules, tablets, pills, powders, andgranules. In such embodiments, the active compound may be admixed withone or more inert diluent such as sucrose, lactose, or starch. Suchdosage forms may also comprise, as in normal practice, additionalsubstances other than inert diluents, e.g., lubricating agents such asmagnesium stearate. In the case of capsules, tablets, and pills, thedosage forms may also comprise buffering agents and can additionally beprepared with enteric coatings.

Preparation of an activated fatty acid in solid dosage form may vary.For example, in one embodiment, a liquid or gelatin formulation of theactivated fatty acid may be prepared by combining the activated fattyacid with one or more fatty acid diluent, such as those described above,and adding a thickening agent to the liquid mixture to form a gelatin.The gelatin may then be encapsulated in unit dosage form to form acapsule. In another exemplary embodiment, an oily preparation of anactivated fatty acid prepared as described above may be lyophilized tofor a solid that may be mixed with one or more pharmaceuticallyacceptable excipient, carrier or diluent to form a tablet, and in yetanother embodiment, the activated fatty acid of an oily preparation maybe crystallized to from a solid which may be combined with apharmaceutically acceptable excipient, carrier or diluent to form atablet.

Further embodiments which may be useful for oral administration ofactivated fatty acids include liquid dosage forms. In such embodiments,a liquid dosage may include a pharmaceutically acceptable emulsion,solution, suspension, syrup, and elixir containing inert diluentscommonly used in the art, such as water. Such compositions may alsocomprise adjuvants, such as wetting agents, emulsifying and suspendingagents, and sweetening, flavoring, and perfuming agents.

In still further embodiments, activated fatty acids of the invention canbe formulated as a depot preparation. Such long acting formulations canbe administered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Depot injections can beadministered at about 1 to about 6 months or longer intervals. Thus, forexample, the compounds can be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

Other suitable diluents for injectable formulations include, but are notlimited to those described below:

Vegetable oil: As used herein, the term “vegetable oil” refers to acompound, or mixture of compounds, formed from ethoxylation of vegetableoil, wherein at least one chain of polyethylene glycol is covalentlybound to the vegetable oil. In some embodiments, the fatty acids hasbetween about twelve carbons to about eighteen carbons. In someembodiments, the amount of ethoxylation can vary from about 2 to about200, about 5 to 100, about 10 to about 80, about 20 to about 60, orabout 12 to about 18 of ethylene glycol repeat units. The vegetable oilmay be hydrogenated or unhydrogenated. Suitable vegetable oils include,but are not limited to castor oil, hydrogenated castor oil, sesame oil,corn oil, peanut oil, olive oil, sunflower oil, safflower oil, soybeanoil, benzyl benzoate, sesame oil, cottonseed oil, and palm oil. Othersuitable vegetable oils include commercially available synthetic oilssuch as, but not limited to, Miglyol™ 810 and 812 (available fromDynamit Nobel Chemicals, Sweden) Neobee™ M5 (available from DrewChemical Corp.), Alofine™ (available from Jarchem Industries), theLubritab™ series (available from JRS Pharma), the Sterotex™ (availablefrom Abitec Corp.), Softisan™ 154 (available from Sasol), Croduret™(available from Croda), Fancol™ (available from the Fanning Corp.),Cutina™ HR (available from Cognis), Simulsol™ (available from CJPetrow), EmCon™ CO (available from Amisol Co.), Lipvol™ CO, SES, andHS-K (available from Lipo), and Sterotex™ HM (available from AbitecCorp.). Other suitable vegetable oils, including sesame, castor, corn,and cottonseed oils, include those listed in R. C. Rowe and P. J.Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th ed., which isincorporated herein by reference in its entirety. Suitablepolyethoxylated vegetable oils, include but are not limited to,Cremaphor™ EL or RH series (available from BASF), Emulphor™ EL-719(available from Stepan products), and Emulphor™ EL-620P (available fromGAF).

Mineral oils: As used herein, the term “mineral oil” refers to bothunrefined and refined (light) mineral oil. Suitable mineral oilsinclude, but are not limited to, the Avatech™ grades (available fromAvatar Corp.), Drakeol™ grades (available from Penreco), Sirius™ grades(available from Shell), and the Citation™ grades (available from AvaterCorp.).

Castor oils: As used herein, the term “castor oil”, refers to a compoundformed from the ethoxylation of castor oil, wherein at least one chainof polyethylene glycol is covalently bound to the castor oil. The castoroil may be hydrogenated or unhydrogenated. Synonyms for polyethoxylatedcastor oil include, but are not limited to polyoxyl castor oil,hydrogenated polyoxyl castor oil, mcrogolglyceroli ricinoleas,macrogolglyceroli hydroxystearas, polyoxyl 35 castor oil, and polyoxyl40 hydrogenated castor oil. Suitable polyethoxylated castor oilsinclude, but are not limited to, the Nikkol™ HCO series (available fromNikko Chemicals Co. Ltd.), such as Nikkol HCO-30, HC-40, HC-50, andHC-60 (polyethylene glycol-30 hydrogenated castor oil, polyethyleneglycol-40 hydrogenated castor oil, polyethylene glycol-50 hydrogenatedcastor oil, and polyethylene glycol-60 hydrogenated castor oil,Emulphor™ EL-719 (castor oil 40 mole-ethoxylate, available from StepanProducts), the Cremophore™ series (available from BASF), which includesCremophore RH40, RH60, and EL35 (polyethylene glycol-40 hydrogenatedcastor oil, polyethylene glycol-60 hydrogenated castor oil, andpolyethylene glycol-35 hydrogenated castor oil, respectively), and theEmulgin® RO and HRE series (available from Cognis PharmaLine). Othersuitable polyoxyethylene castor oil derivatives include those listed inR. C. Rowe and P. J. Shesky, Handbook of Pharmaceutical Excipients,(2006), 5th ed., which is incorporated herein by reference in itsentirety.

Sterol: As used herein, the term “sterol” refers to a compound, ormixture of compounds, derived from the ethoxylation of sterol molecule.Suitable polyethoyxlated sterols include, but are not limited to, PEG-24cholesterol ether, Solulan™ C-24 (available from Amerchol); PEG-30cholestanol, Nikkol™ DHC (available from Nikko); Phytosterol, GENEROL™series (available from Henkel); PEG-25 phyto sterol, Nikkol™ BPSH-25(available from Nikko); PEG-5 soya sterol, Nikkol™ BPS-5 (available fromNikko); PEG-10 soya sterol, Nikkol™ BPS-10 (available from Nikko);PEG-20 soya sterol, Nikkol™ BPS-20 (available from Nikko); and PEG-30soya sterol, Nikkol™ BPS-30 (available from Nikko). As used herein, theterm “PEG” refers to polyethylene glycol.

Polyethylene glycol: As used herein, the term “polyethylene glycol” or“PEG” refers to a polymer containing ethylene glycol monomer units offormula —O—CH₂—CH₂—. Suitable polyethylene glycols may have a freehydroxyl group at each end of the polymer molecule, or may have one ormore hydroxyl groups etherified with a lower alkyl, e.g., a methylgroup. Also suitable are derivatives of polyethylene glycols havingesterifiable carboxy groups. Polyethylene glycols useful in the presentinvention can be polymers of any chain length or molecular weight, andcan include branching. In some embodiments, the average molecular weightof the polyethylene glycol is from about 200 to about 9000. In someembodiments, the average molecular weight of the polyethylene glycol isfrom about 200 to about 5000. In some embodiments, the average molecularweight of the polyethylene glycol is from about 200 to about 900. Insome embodiments, the average molecular weight of the polyethyleneglycol is about 400. Suitable polyethylene glycols include, but are notlimited to polyethylene glycol-200, polyethylene glycol-300,polyethylene glycol-400, polyethylene glycol-600, and polyethyleneglycol-900. The number following the dash in the name refers to theaverage molecular weight of the polymer. In some embodiments, thepolyethylene glycol is polyethylene glycol-400. Suitable polyethyleneglycols include, but are not limited to the Carbowax™ and Carbowax™Sentry series (available from Dow), the Lipoxol™ series (available fromBrenntag), the Lutrol™ series (available from BASF), and the Pluriol™series (available from BASF).

Propylene glycol fatty acid ester: As used herein, the term “propyleneglycol fatty acid ester” refers to an monoether or diester, or mixturesthereof, formed between propylene glycol or polypropylene glycol and afatty acid. Fatty acids that are useful for deriving propylene glycolfatty alcohol ethers include, but are not limited to, those definedherein. In some embodiments, the monoester or diester is derived frompropylene glycol. In some embodiments, the monoester or diester hasabout 1 to about 200 oxypropylene units. In some embodiments, thepolypropylene glycol portion of the molecule has about 2 to about 100oxypropylene units. In some embodiments, the monoester or diester hasabout 4 to about 50 oxypropylene units. In some embodiments, themonoester or diester has about 4 to about 30 oxypropylene units.Suitable propylene glycol fatty acid esters include, but are not limitedto, propylene glycol laurates: Lauroglycol™ FCC and 90 (available fromGattefosse); propylene glycol caprylates: Capryol™ PGMC and 90(available from Gatefosse); and propylene glycol dicaprylocaprates:Labrafac™ PG (available from Gatefosse).

Stearoyl macrogol glyceride: Stearoyl macrogol glyceride refers to apolyglycolized glyceride synthesized predominately from stearic acid orfrom compounds derived predominately from stearic acid, although otherfatty acids or compounds derived from other fatty acids may used in thesynthesis as well. Suitable stearoyl macrogol glycerides include, butare not limited to, Gelucire® 50/13 (available from Gattefossé).

In some embodiments, the diluent component comprises one or more ofmannitol, lactose, sucrose, maltodextrin, sorbitol, xylitol, powderedcellulose, microcrystalline cellulose, carboxymethylcellulose,carboxyethylcellulose, methylcellulose, ethylcellulose,hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodiumstarch glycolate, pregelatinized starch, a calcium phosphate, a metalcarbonate, a metal oxide, or a metal aluminosilicate.

Exemplary excipients or carriers for use in solid and/or liquid dosageforms include, but are not limited to:

Sorbitol: Suitable sorbitols include, but are not limited to,PharmSorbidex E420 (available from Cargill), Liponic 70-NC and 76-NC(available from Lipo Chemical), Neosorb (available from Roquette),Partech SI (available from Merck), and Sorbogem (available from SPIPolyols).

Starch, sodium starch glycolate, and pregelatinized starch include, butare not limited to, those described in R. C. Rowe and P. J. Shesky,Handbook of Pharmaceutical Excipients, (2006), 5th ed., which isincorporated herein by reference in its entirety.

Disintegrant: The disintegrant may include one or more of croscarmellosesodium, carmellose calcium, crospovidone, alginic acid, sodium alginate,potassium alginate, calcium alginate, an ion exchange resin, aneffervescent system based on food acids and an alkaline carbonatecomponent, clay, talc, starch, pregelatinized starch, sodium starchglycolate, cellulose floc, carboxymethylcellulose,hydroxypropylcellulose, calcium silicate, a metal carbonate, sodiumbicarbonate, calcium citrate, or calcium phosphate.

Still further embodiments of the invention include activated fatty acidsadministered in combination with other active such as, for example,adjuvants, protease inhibitors, or other compatible drugs or compoundswhere such combination is seen to be desirable or advantageous inachieving the desired effects of the methods described herein.

This invention and embodiments illustrating the method and materialsused may be further understood by reference to the followingnon-limiting examples.

Example 1 Preparation of (E)-9-nitro-octadec-9-enoic acid

Commercially available 9-bromononanol was oxidized using Jones' reagent,chromium trioxide (CrO₃) in concentrated sulfuric acid (H₂SO₄), 67%, toform a carboxylic acid protected as an allyl ester (92% yield) and wasnitrated using the Kornblum method, silver nitrate (AgNO₂) in diethylether (Et₂O), to form 9-nitro-nonanoic acid, allyl ester, in an overallyield of 42%. Nitroaldol condensation was then carried out by combiningthis intermediate with commercially available nonyl aldehyde in thepresence of a catalytic amount of (10 mol %) of DBU to produceβ-hydroxynitro (81% yield) as a 1:1 mixture of diastereomers. Theβ-hydroxynitro ester intermediate was acetylated in acetic anhydridewith a catalytic amount of p-toluenesulfonic acid to produce aβ-acetoxynitro ester intermediate in high yield, and the nitroalkene wasgenerated by from the β-acetoxynitro ester intermediate by base-inducedelimination with azeotropic removal of water in 0.5 equivalence ofsodium carbonate. The stereoselectively clean (E)-isomer nitroalkene wasproduced in 84% yield and did not require isomerization or deconjugationof double bonds to form allylic nitroalkanes. A free acid of theproduced nitroalkene was accomplished by palladium catalyzedisomerization in the presence of formic acid to produce the free acid(E)-9-nitro-octadec-9-enoic acid in 95% yield. Overall yield fromcommercially available starting products was 56%. Because of the basesensitivity of nitroalkenes acidic conditions were consistentlythroughout both reaction and work-up were possible.

Example 2 Production of (Z)-isomers

(Z)-9-nitro-octadec-9-enoic was formed from the(E)-9-nitro-octadec-9-enoic acid using the Ono method as described inOno, N, et al. J. Chem. Soc., Chem. Commun. 1987, 1551-1551 andSharpless et al., Am. Chem. Soc. 1973, 95, 2697-2699, both of which arehereby incorporated by reference in their entireties, at about 80% toabout 90% yield.

1. A compound comprising a non-naturally occurring, unsaturated orpolyunsaturated fatty acid having one or more electron withdrawing groupassociated with at least one carbon-carbon double bond or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein the non-naturally occurring, unsaturated or polyunsaturatedfatty acid comprises an aliphatic chain having an odd number of carbons.3. The compound of claim 1, wherein the non-naturally occurringunsaturated or polyunsaturated fatty acid comprises an aliphatic chainhaving 5 to 23 carbons.
 4. The compound of claim 1, wherein thenon-naturally occurring unsaturated or polyunsaturated fatty acidcomprises an aliphatic chain having 5, 7, 9, 11, 13, 15, 17, 19, 21 or23 carbons.
 5. The compound of claim 1, wherein the non-naturallyoccurring unsaturated or polyunsaturated fatty acid is selected from aglycolipid, a glycerolipid, a phospholipid and a cholesterol ester. 6.The compound of claim 1, wherein the one or more electron withdrawinggroup is selected from aldehyde (—COH), acyl (—COR), carbonyl (—CO),carboxylic acid (—COOH), ester (—COOR), halides (—Cl, —F, —Br, —I),fluoromethyl (—CFO, allyl fluoride (—CH═CHCH₂F), cyano (—CN), sulfoxide(—SOR), sulfonyl (—SO₂R), sulfonic acid (—SO₃H), 1°, 2° and 3° ammonium(—NR₃ ⁺), and nitro (—NO₂), wherein R is a hydrogen, methyl or C₂-C₆alkyl.
 7. The compound of claim 1, wherein the one or more electronwithdrawing group is a nitro (—NO₂) group.
 8. The compound of claim 1,wherein the one or more electron withdrawing group is positioned on analpha carbon of a carbon-carbon double bond of the non-naturallyoccurring, unsaturated or polyunsaturated fatty acid.
 9. The compound ofclaim 1, wherein the one or more electron withdrawing group ispositioned on a beta carbon of a carbon-carbon double bond of thenon-naturally occurring, unsaturated or polyunsaturated fatty acid. 10.The compound of claim 1, wherein the one or more electron withdrawinggroup is positioned on a gamma carbon of a carbon-carbon double bond ofthe non-naturally occurring, unsaturated or polyunsaturated fatty acid.11. The compound of claim 1, wherein at least one of the one or moreelectron withdrawing group is an electron withdrawing vinyl group or anelectron withdrawing allylic group.
 12. The compound of claim 1, whereina carbon-carbon double bond associated with the one or more electronwithdrawing group is in cis configuration.
 13. The compound of claim 1,wherein a carbon-carbon double bond associated with the one or moreelectron withdrawing group is in trans configuration.
 14. The compoundof claim 1, wherein the one or more electron withdrawing group is in anabsolute stereochemistry of R at an sp³ chiral/stereogenic center. 15.The compound of claim 1, wherein the one or more electron withdrawinggroup is in an absolute stereochemistry of S at an sp³chiral/stereogenic center.
 16. The compound of claim 1, wherein acarbon-carbon double bond occurs at any carbon of the aliphatic chain ofthe non-naturally occurring, unsaturated or polyunsaturated fatty acid.17. The compound of claim 1, wherein the non-naturally occurring,unsaturated or polyunsaturated fatty acid is a fatty acid with two ormore conjugated carbon-carbon double bonds.
 18. The compound of claim17, wherein at least one of the one or more electron withdrawing groupis at any carbon in the two or more conjugated carbon-carbon doublebonds.
 19. The compound of claim 1, wherein at least one of the one ormore electron withdrawing group is positioned at C-9, C-10, C-12, C-13or a combination thereof.
 20. The compound of claim 1, furthercomprising one or more non-carbon-carbon linkage selected from an esterlinkage, an ether linkage, and a vinyl ether linkage.
 21. The compoundof claim 1, further comprising one or more functional group other thanan electron withdrawing group positioned at any carbon of thenon-naturally occurring, unsaturated or polyunsaturated fatty acid. 22.The compound of claim 1, wherein the non-naturally occurring,unsaturated or polyunsaturated fatty acid having one or more electronwithdrawing group or a pharmaceutically acceptable salt thereof furthercomprises a pharmaceutically acceptable carrier or excipient.
 23. Thecompound of claim 22, further comprising one or more of diluents,fillers, disintegrants, binders, lubricants, surfactants, hydrophobicvehicles, water soluble vehicles, emulsifiers, buffers, humectants,moisturizers, solubilizers, antioxidants, preservatives or combinationsthereof.
 24. The compound of claim 22, wherein the non-naturallyoccurring, unsaturated or polyunsaturated fatty acid having one or moreelectron withdrawing group or a pharmaceutically acceptable salt thereoffurther comprising a pharmaceutically acceptable carrier or excipient isformulated as a solid, solution, powder, fluid emulsion, fluidsuspension, semi-solid or dry powder.
 25. A compound comprising anunsaturated or polyunsaturated fatty acid having one or more electronwithdrawing group associated with at least one double bond or apharmaceutically acceptable salt thereof, with the proviso that theelectron withdrawing group associated with the at least one double bondis not a nitro (—NO₂) group.
 26. The compound of claim 25, wherein theunsaturated or polyunsaturated fatty acid comprises a naturallyoccurring fatty acid or derivative thereof.
 27. The compound of claim25, wherein the unsaturated or polyunsaturated fatty acid comprises analiphatic carbon chain having an even number of carbons.
 28. Thecompound of claim 25, wherein the unsaturated or polyunsaturated fattyacid comprises an aliphatic carbon chain having from 4 to 24 carbons.29. The compound of claim 25, wherein the unsaturated or polyunsaturatedfatty acid comprises an aliphatic carbon chain having from 12 to 18carbons.
 30. The compound of claim 25, wherein the unsaturated orpolyunsaturated fatty acid is selected from ω-2, ω-3, ω-4,ω-5, ω-6, ω-7,ω-8, ω-9 fatty acids and equivalents and derivatives thereof.
 31. Thecompound of claim 25, wherein the unsaturated or polyunsaturated fattyacid is selected from linolenic acid, alpha-linolenic acid,eicosapentanoic acid, docosapentaenoic acid, docosahexaenoic acid,stearidonic acid, myristoleic acid, linoleic acid, gamma-linoleic acid,dihomo-gamma-linoleic acid, arachidonic acid, palmitoleic acid, oleicacid, erucic acid and equivalents and derivatives thereof.
 32. Thecompound of claim 25, wherein the unsaturated fatty acid is selectedfrom linoleic acid, oleic acid, arachidonic acid or a derivativethereof.
 33. The compound of claim 25, wherein the unsaturated fattyacid is selected from a glycolipid, a glycerolipid, a phospholipid and acholesterol ester.
 34. The compound of claim 25, wherein the at leastone electron withdrawing group is positioned at C-9, C-10, C-12, C-13 ora combination thereof.
 35. The compound of claim 25, further comprisingone or more non-carbon-carbon linkage selected from an ester linkage, anether linkage, a vinyl ether linkage or a combination thereof.
 36. Thecompound of claim 25, wherein the one or more electron withdrawing groupis selected from aldehyde (—COH), acyl (—COR), carbonyl (—CO),carboxylic acid (—COOH), ester (—COOR), halides (—Cl, —F, —Br, —I),fluoromethyl (—CF_(n)), allyl fluoride (—CH═CHCH₂F), cyano (—CN),sulfoxide (—SOR), sulfonyl (—SO₂R), sulfonic acid (—SO₃H), and 1°, 2°and 3° ammonium (—NR₃ ⁺), wherein R is a hydrogen, methyl or C₂-C₆alkyl.
 37. The compound of claim 25, wherein the one or more electronwithdrawing group is positioned on an alpha carbon of a carbon-carbondouble bond of the unsaturated or polyunsaturated fatty acid.
 38. Thecompound of claim 25, wherein the one or more electron withdrawing groupis positioned on a beta carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid.
 39. The compound of claim 25,wherein the one or more electron withdrawing group is positioned on agamma carbon of a carbon-carbon double bond of the unsaturated orpolyunsaturated fatty acid.
 40. The compound of claim 25, wherein atleast one of the one or more electron withdrawing group is an electronwithdrawing vinyl group or an electron withdrawing allylic group. 41.The compound of claim 25, wherein a carbon-carbon double bond associatedwith the one or more electron withdrawing group is in cis configuration.42. The compound of claim 25, wherein a carbon-carbon double bondassociated with the one or more electron withdrawing group is in transconfiguration.
 43. The compound of claim 25, wherein the one or moreelectron withdrawing group is in an absolute stereochemistry of R at ansp³ chiral/stereogenic center.
 44. The compound of claim 25, wherein theone or more electron withdrawing group is in an absolute stereochemistryof S at an sp³ chiral/stereogenic center.
 45. The compound of claim 25,wherein a carbon-carbon double bond occurs at any carbon of thealiphatic chain of the unsaturated or polyunsaturated fatty acid. 46.The compound of claim 25, wherein the non-naturally occurring,unsaturated or polyunsaturated fatty acid is a fatty acid with two ormore conjugated carbon-carbon double bonds.
 47. The compound of claim46, wherein at least one of the one or more electron withdrawing groupis at any carbon in the two or more conjugated carbon-carbon doublebonds.
 48. The compound of claim 25, wherein the unsaturated orpolyunsaturated fatty acid having one or more electron withdrawing groupassociated with at least one double bond or a pharmaceuticallyacceptable salt thereof, further comprises a pharmaceutically acceptablecarrier or excipient.
 49. The compound of claim 48, further comprisingone or more of diluents, fillers, disintegrants, binders, lubricants,surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers,buffers, humectants, moisturizers, solubilizers, antioxidants,preservatives or combinations thereof.
 50. The compound of claim 48,wherein the unsaturated or polyunsaturated fatty acid having one or moreelectron withdrawing group associated with at least one double bond or apharmaceutically acceptable salt thereof further comprising apharmaceutically acceptable carrier or excipient is formulated as asolid, solution, powder, fluid emulsion, fluid suspension, semi-solid ordry powder.
 51. A method for treating a condition comprisingadministering an effective amount of an unsaturated or polyunsaturatedfatty acid having one or more electron withdrawing group associated withat least one double bond with the proviso that the electron withdrawinggroup is not nitro (—NO₂) or a pharmaceutically acceptable salt thereofto a subject in need of treatment.
 52. The method of claim 51, whereinthe one or more electron withdrawing group is selected from aldehyde(—COH), acyl (—COR), carbonyl (—CO), carboxylic acid (—COOH), ester(—COOR), halides (—Cl, —F, —Br, —I), fluoromethyl (—CF_(n)), allylfluoride (—CH═CHCH₂F), cyano (—CN), sulfoxide (—SOR), sulfonyl (—SO₂R),sulfonic acid (—SO₃H), and 1°, 2°, and 3° ammonium (—NR₃ ⁺), wherein Ris a hydrogen, methyl or C₂-C₆ alkyl.
 53. The method of claim 51,wherein the unsaturated or polyunsaturated fatty acid comprises analiphatic carbon chain having from 12 to 18 carbons.
 54. The method ofclaim 51, wherein the unsaturated or polyunsaturated fatty acid isselected from ω-2, ω-3, ω-4, ω-5, ω-6, ω-7, ω-8, or ω-9 fatty acids andequivalents and derivatives thereof.
 55. The method of claim 51, whereinthe unsaturated or polyunsaturated fatty acid is selected from linolenicacid, alpha-linolenic acid, eicosapentanoic acid, docosapentaenoic acid,docosahexaenoic acid, stearidonic acid, myristoleic acid, linoleic acid,gamma-linoleic acid, dihomo-gamma-linoleic acid, arachidonic acid,palmitoleic acid, oleic acid, erucic acid and equivalents andderivatives thereof.
 56. The method of claim 51, wherein the one or moreelectron withdrawing group is positioned on an alpha carbon of acarbon-carbon double bond of the unsaturated or polyunsaturated fattyacid.
 57. The method of claim 51, wherein the one or more electronwithdrawing group is positioned on a beta carbon of a carbon-carbondouble bond of the unsaturated or polyunsaturated fatty acid.
 58. Themethod of claim 51, wherein the one or more electron withdrawing groupis positioned on a gamma carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid.
 59. The method of claim 51,wherein at least one of the one or more electron withdrawing group is anelectron withdrawing vinyl group or an electron withdrawing allylicgroup.
 60. The method of claim 51, wherein a carbon-carbon double bondassociated with the one or more electron withdrawing group is in cisconfiguration.
 61. The method of claim 51, wherein a carbon-carbondouble bond associated with the one or more electron withdrawing groupis in trans configuration.
 62. The method of claim 51, wherein theeffective amount comprises a mixture of unsaturated or polyunsaturatedfatty acids having one or more electron withdrawing group associatedwith at least one double bond wherein the mixture comprises electronwithdrawing group positioned on alpha, beta, and gamma carbon of acarbon-carbon double bonds of the unsaturated or polyunsaturated fattyacids.
 63. The method of claim 51, wherein the condition is selectedfrom arterial stenosis, burns, hypertension, obesity, neurodegenerativedisorders, skin disorders, arthritis, autoimmune disease,autoinflammatory disease, lupus, Lyme's disease, gout, sepsis,hyperthermia, ulcers, enterocolitis, osteoporosis, viral or bacterialinfections, cytomegalovirus, periodontal disease, glomerulonephritis,sarcoidosis, lung disease, chronic lung injury, respiratory distress,lung inflammation, fibrosis of the lung, asthma, acquired respiratorydistress syndrome, tobacco induced lung disease, granuloma formation,fibrosis of the liver, graft vs. host disease, postsurgicalinflammation, coronary and peripheral vessel restenosis followingangioplasty, stent placement or bypass graft, acute and chronicleukemia, B lymphocyte leukemia, neoplastic diseases, arteriosclerosis,atherosclerosis, myocardial inflammation, psoriasis, immunodeficiency,disseminated intravascular coagulation, systemic sclerosis, amyotrophiclateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer'sdisease, encephalomyelitis, edema, inflammatory bowel disease, hyper IgEsyndrome, cancer metastasis or growth, adoptive immune therapy,reperfusion syndrome, radiation burns, and alopecia.
 64. A method fortreating a condition comprising administering an effective amount of anon-naturally occurring, unsaturated or polyunsaturated fatty acidhaving one or more electron withdrawing group or a pharmaceuticallyacceptable salt thereof to a subject in need of treatment.
 65. Themethod of claim 64, wherein the non-naturally occurring, unsaturated orpolyunsaturated fatty acid comprises an aliphatic chain having an oddnumber of carbons.
 66. The method of claim 64, wherein the non-naturallyoccurring unsaturated or polyunsaturated fatty acid comprises analiphatic chain having 5 to 23 carbons.
 67. The method of claim 64,wherein the one or more electron withdrawing group is selected fromaldehyde (—COH), acyl (—COR), carbonyl (—CO), carboxylic acid (—COOH),ester (—COOR), halides (—Cl, —F, —Br, —I), fluoromethyl (—CF_(n)), allylfluoride (—CH═CHCH₂F), cyano (—CN), sulfoxide (—SOR), sulfonyl (—SO₂R),sulfonic acid (—SO₃H), and 1°, 2° and 3° ammonium (—NR₃ ⁺), and nitro(—NO₂) wherein R is a hydrogen, methyl or C₂-C₆ alkyl.
 68. The method ofclaim 64, wherein the one or more electron withdrawing group ispositioned on an alpha carbon of a carbon-carbon double bond of theunsaturated or polyunsaturated fatty acid.
 69. The method of claim 64,wherein the one or more electron withdrawing group is positioned on abeta carbon of a carbon-carbon double bond of the unsaturated orpolyunsaturated fatty acid.
 70. The method of claim 64, wherein the oneor more electron withdrawing group is positioned on a gamma carbon of acarbon-carbon double bond of the unsaturated or polyunsaturated fattyacid.
 71. The method of claim 64, wherein at least one of the one ormore electron withdrawing group is an electron withdrawing vinyl groupor an electron withdrawing allylic group.
 72. The method of claim 64,wherein a carbon-carbon double bond associated with the one or moreelectron withdrawing group is in cis configuration.
 73. The method ofclaim 64, wherein a carbon-carbon double bond associated with the one ormore electron withdrawing group is in trans configuration.
 74. Themethod of claim 64, wherein the effective amount comprises a mixture ofunsaturated or polyunsaturated fatty acids having one or more electronwithdrawing group associated with at least one double bond wherein themixture comprises electron withdrawing group positioned on alpha, beta,and gamma carbon of a carbon-carbon double bonds of the unsaturated orpolyunsaturated fatty acids.
 75. The method of claim 64, wherein thecondition is selected from arterial stenosis, burns, hypertension,obesity, neurodegenerative disorders, skin disorders, arthritis,autoimmune disease, autoinflammatory disease, lupus, Lyme's disease,gout, sepsis, hyperthermia, ulcers, enterocolitis, osteoporosis, viralor bacterial infections, cytomegalovirus, periodontal disease,glomerulonephritis, sarcoidosis, lung disease, chronic lung injury,respiratory distress, lung inflammation, fibrosis of the lung, asthma,acquired respiratory distress syndrome, tobacco induced lung disease,granuloma formation, fibrosis of the liver, graft vs. host disease,postsurgical inflammation, coronary and peripheral vessel restenosisfollowing angioplasty, stent placement or bypass graft, acute andchronic leukemia, B lymphocyte leukemia, neoplastic diseases,arteriosclerosis, atherosclerosis, myocardial inflammation, psoriasis,immunodeficiency, disseminated intravascular coagulation, systemicsclerosis, amyotrophic lateral sclerosis, multiple sclerosis,Parkinson's disease, Alzheimer's disease, encephalomyelitis, edema,inflammatory bowel disease, hyper IgE syndrome, cancer metastasis orgrowth, adoptive immune therapy, reperfusion syndrome, radiation burns,and alopecia.